Journal: Cardiovasc Diabetol

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Abstract

Visit-to-visit HbA variability is associated with in-stent restenosis in patients with type 2 diabetes after percutaneous coronary intervention.

Yang CD, Shen Y, Lu L, Yang ZK, ... Ding FH, Wang XQ
Background
Patients with type 2 diabetes are under substantially higher risk of in-stent restenosis (ISR) after coronary stent implantation. We sought to investigate whether visit-to-visit HbA variability is a potential predictor of ISR in diabetic patients after stent implantation.
Methods
We consecutively enrolled type 2 diabetic patients who underwent successful elective percutaneous coronary intervention and performed follow-up coronary angiography after around 12 months. The incidence of ISR and its relationship with visit-to-visit HbA variability, expressed as coefficient of variation (CV), standard deviation (SD) and variability independent of the mean (VIM), were studied. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of HbA variability for ISR.
Results
From September 2014 to July 2018 in Ruijin Hospital, a total of 420 diabetic patients (688 lesions) after stent implantation were included in the final analysis. During a mean follow-up of 12.8 ± 1.3 months, the incidence of ISR was 8.6%, which was significantly increased in patients with higher CV of HbA (P = 0.001). The mean diameter stenosis (DS), net luminal loss and net luminal gain were 22.9 ± 16.8%, 0.42 ± 0.88 mm and 1.66 ± 0.83 mm, respectively. Greater DS was observed in subjects with higher tertiles of CV of HbA (P < 0.001), and this trend was more prominent in patients with optimal glycemic control (HbA ≤ 7%) in the baseline. In multivariate analysis, HbA variability was independently associated with incidence of ISR after adjustment for traditional risk factors and mean HbA (HR: 3.00 [95% CI 1.14-7.92] for highest vs. lowest tertile). Inclusion of CV of HbA led to a better risk stratification accuracy. Assessing HbA variability by SD or VIM yielded similar findings.
Conclusions
This study suggests that visit-to-visit HbA variability is an independent predictor of incidence of ISR in patients with type 2 diabetes after stent implantation. Trial registration NCT02089360: NCT.



Cardiovasc Diabetol: 03 Sep 2020; 19:133
Yang CD, Shen Y, Lu L, Yang ZK, ... Ding FH, Wang XQ
Cardiovasc Diabetol: 03 Sep 2020; 19:133 | PMID: 32887588
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Abstract

Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach.

Nesti L, Pugliese NR, Sciuto P, Natali A

The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.



Cardiovasc Diabetol: 04 Sep 2020; 19:134
Nesti L, Pugliese NR, Sciuto P, Natali A
Cardiovasc Diabetol: 04 Sep 2020; 19:134 | PMID: 32891175
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Abstract

Macrophage accumulation within coronary arterial wall in diabetic patients with acute coronary syndrome: a study with in-vivo intravascular imaging modalities.

Kogo T, Hiro T, Kitano D, Takayama T, ... Sudo M, Okumura Y
Background and aims
Macrophage accumulation in arteriosclerotic plaque of coronary arteries is involved in plaque destabilization. Atherosclerosis has been known to be progressive in patients with type 2 diabetes mellitus (DM). This study compared the features of 3-dimensional (3D) spatial distribution of macrophage accumulation within coronary artery wall between acute coronary syndrome (ACS) patients with DM (n = 20) and those without (non-DM, n = 20) by using intravascular ultrasound (IVUS) and optical coherence tomography (OCT).
Methods
The OCT-derived macrophage accumulation was measured within the proximal left anterior-descending artery. This measurement was performed for the whole vessel segment of interest, higher shear stress region (flow divider side) and lower shear stress region (the opposite side).
Results
Normalized macrophage accumulation per unit length of the whole segment of interest was significantly larger in ACS patients with DM than without. In non-DM patients, macrophage density per IVUS-derived plaque volume was significantly higher in high shear stress region compared to low shear stress region, however, there was no significant difference between the two regions in DM patients. The macrophage density in the low shear stress region was significantly higher in the DM group than in the non-DM group. A multivariate analysis showed that the presence of DM was a major determinant for macrophage distribution.
Conclusions
Macrophage accumulation was more abundant and homogeneous within coronary arterial wall in DM patients with ACS compared to non-DM patients, suggesting that plaque destabilization may occur more widely throughout coronary wall in DM patients.



Cardiovasc Diabetol: 04 Sep 2020; 19:135
Kogo T, Hiro T, Kitano D, Takayama T, ... Sudo M, Okumura Y
Cardiovasc Diabetol: 04 Sep 2020; 19:135 | PMID: 32891145
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Abstract

MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy.

Ait-Aissa K, Nguyen QM, Gabani M, Kassan A, ... Chen C, Kassan M

The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.



Cardiovasc Diabetol: 08 Sep 2020; 19:136
Ait-Aissa K, Nguyen QM, Gabani M, Kassan A, ... Chen C, Kassan M
Cardiovasc Diabetol: 08 Sep 2020; 19:136 | PMID: 32907629
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Abstract

Triglyceride glucose index for the detection of asymptomatic coronary artery stenosis in patients with type 2 diabetes.

Thai PV, Tien HA, Van Minh H, Valensi P
Background
Triglyceride Glucose (TyG) index has been associated with an increased risk in cardiovascular events. Silent coronary disease is common in patients with type 2 diabetes. In Vietnam, a low-middle income country, the burden of cardiovascular disease is growing simultaneously with the epidemiologic transition. Our aim was to assess the prevalence of coronary stenoses (CS) in patients with type 2 diabetes and no history or symptom of cardiovascular disease and to investigate the association between TyG index and cardiovascular risk factors and both the presence and severity of CS. Futhermore, we assessed the value of TyG index in predicting subclinical CS.
Methods
This was a cross-sectional observational study. We recruited 166 patients at Ninh Thuan General Hospital, Vietnam. TyG index and HOMA-IR were calculated, and a coronary computed tomography angiography (CCTA) was performed.
Results
The population was classified according to tertiles of TyG index. The highest TyG values were associated with higher BMI, waist circumference, total cholesterol, LDL-cholesterol, triglycerides, plasma glucose, HbA1c levels and HOMA-IR, lower HDL-cholesterol, a higher incidence of metabolic syndrome and less frequent physical activity (p < 0.05 to < 0.0001). TyG index correlated with logHOMA-IR (p < 0.0001). CS ≥ 50% were present in 60 participants and 32 had coronary artery stenosis ≥ 70%. TyG index and HOMA-IR were significantly higher in patients with CS ≥ 70%. The number of narrowed coronary arteries and the degree of stenosis were associated with higher TyG index levels (p = 0.04 and < 0.005 respectively). A TyG index ≥ 10 was significantly associated with an increased risk of multiple coronary artery disease and of more severe CS. After adjusting for confounding factors, including logHOMA-IR, these risks remained mostly significant. A TyG index threshold at 10 resulted in 57% sensitivity and 75% specificity for predicting the presence of CS ≥ 70%. In subgroup analysis TyG index ≥ 10 was associated with an increased risk in CS ≥ 70% in patients treated with statin or antiplatelet therapy.
Conclusion
More than one third of asymptomatic patients with type 2 diabetes had significant CS on CCTA. TyG index may be considered as a marker for insulin resistance and increased TyG index could identify patients with high risk of coronary artery stenoses and is associated with the number and the severity of artery stenoses.



Cardiovasc Diabetol: 11 Sep 2020; 19:137
Thai PV, Tien HA, Van Minh H, Valensi P
Cardiovasc Diabetol: 11 Sep 2020; 19:137 | PMID: 32919465
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Abstract

Long-term trajectories of BMI predict carotid stiffness and plaque volume in type 2 diabetes older adults: a cohort study.

Botvin Moshe C, Haratz S, Ravona-Springer R, Heymann A, ... Schnaider Beeri M, Tanne D
Background
High body mass index (BMI) is a risk factor for type 2 diabetes and cardiovascular disease. However, its relationships with indices of carotid stiffness and plaque volume are unclear. We investigated associations of long-term measurements of BMI with indices of carotid stiffness and atherosclerosis among non-demented diabetes patients from the Israel Diabetes and Cognitive Decline (IDCD) study.
Methods
Carotid ultrasound indices [carotid intima media thickness (cIMT), distensibility, elastography and plaque volume] were assessed in N = 471 participants. Mean BMI across all MHS diabetes registry measurements and trajectories of BMI were calculated. BMI was categorized into three trajectory groups representing: a relatively stable normal weight (n = 185, 44%), overweight trajectory (n = 188, 44.8%) and a trajectory of obesity (n = 47, 11.2%). Linear and logistic regressions estimated associations of carotid indices with mean BMI and BMI trajectories.
Results
Compared to the normal weight trajectory, an obesity trajectory was associated with carotid distensibility (β = - 3.078, p = 0.037), cIMT (β = 0.095, p = 0.004), and carotid elastography (β = 0.181, p = 0.004) but not with plaque volume (β = 0.066, p = 0.858). Compared with the normal weight trajectory, an obesity trajectory was associated with increased odds for impaired carotid distensibility (OR = 2.790, p = 0.033), impaired cIMT (OR = 5.277, p = 0.001) and large carotid plaque volume (OR = 8.456, p = 0.013) but not with carotid elastography (OR = 1.956, p = 0.140). Mean BMI was linearly associated with Distensibility (β = - 0.275, p = 0.005) and cIMT (β = 0.005, p = 0.026).
Conclusions
Long-term measurements of adiposity are associated with indices of carotid stiffness and plaque volume among older type 2 diabetes adults.



Cardiovasc Diabetol: 14 Sep 2020; 19:138
Botvin Moshe C, Haratz S, Ravona-Springer R, Heymann A, ... Schnaider Beeri M, Tanne D
Cardiovasc Diabetol: 14 Sep 2020; 19:138 | PMID: 32933542
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Abstract

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

Bourron O, Phan F, Diallo MH, Hajage D, ... Amouyal C, Hartemann A
Background
Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes.
Methods
Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model.
Results
At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (β coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004).
Conclusion
In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.



Cardiovasc Diabetol: 17 Sep 2020; 19:140
Bourron O, Phan F, Diallo MH, Hajage D, ... Amouyal C, Hartemann A
Cardiovasc Diabetol: 17 Sep 2020; 19:140 | PMID: 32948184
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Abstract

Positive association between triglyceride glucose index and arterial stiffness in hypertensive patients: the China H-type Hypertension Registry Study.

Li M, Zhan A, Huang X, Hu L, ... Bao H, Cheng X
Background
Data are limited on whether TyG index is an independent predictor of arterial stiffness in hypertensive patients. The purpose of this study was to assess the association between the TyG index and arterial stiffness, and examined whether there were effect modifiers, in hypertensive patients.
Methods
This study included 4718 hypertensive adults, a subset of the China H-type Hypertension Registry Study. The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Arterial stiffness was determined by measuring brachial-ankle pulse wave velocity (baPWV).
Results
The overall mean TyG index was 8.84. Multivariate linear regression analyses showed that TyG index was independently and positively associated with baPWV (β, 1.02; 95% confidence interval [CI] 0.83, 1.20). Consistently, Multiple logistic analyses showed a positive association between TyG index risk of elevated baPWV (> 75th percentile) (odds ratio [OR], 2.12; 95% CI 1.80, 2.50). Analyses using restricted cubic spline confirmed that the associations of TyG index with baPWV and elevated baPWV were linear. Subgroup analyses showed that stronger associations between TyG index and baPWV were detected in men (all P for interaction < 0.05).
Conclusion
TyG index was independently and positively associated with baPWV and elevated baPWV among hypertensive patients, especially in men. The data suggest that TyG index may serve as a simple and effective tool for arterial stiffness risk assessment in daily clinical practice.



Cardiovasc Diabetol: 17 Sep 2020; 19:139
Li M, Zhan A, Huang X, Hu L, ... Bao H, Cheng X
Cardiovasc Diabetol: 17 Sep 2020; 19:139 | PMID: 32948181
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Abstract

Type 2 diabetes is an independent predictor of lowered peak aerobic capacity in heart failure patients with non-reduced or reduced left ventricular ejection fraction.

Abe T, Yokota T, Fukushima A, Kakutani N, ... Kinugawa S, Anzai T
Background
Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients\' peak aerobic capacity.
Methods
We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort.
Results
The mean peak oxygen uptake (VO) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of - 0.93 (- 1.82 to - 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of - 1.05 (- 1.96 to - 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO in CHF patients with non-reduced LVEF and those with reduced LVEF.
Conclusions
T2DM was associated with lowered peak VO in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients\' exercise capacity, and the degree of impact is partly dependent on their LV systolic function.



Cardiovasc Diabetol: 18 Sep 2020; 19:142
Abe T, Yokota T, Fukushima A, Kakutani N, ... Kinugawa S, Anzai T
Cardiovasc Diabetol: 18 Sep 2020; 19:142 | PMID: 32950064
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Abstract

Exposure-weighted scoring for metabolic syndrome and the risk of myocardial infarction and stroke: a nationwide population-based study.

Lee EY, Han K, Kim DH, Park YM, ... Kim MK, Lee SH
Background
Metabolic syndrome (MetS) status changes over time, but few studies have investigated the relationship between the extent or duration of exposure to MetS and the risk of cardiovascular disease (CVD). We investigated the cumulative effects of MetS and its components on the risk of myocardial infarction (MI) and stroke.
Methods
From the Korean National Health Insurance database, 2,644,851 people who received annual health examinations from 2010 to 2013 were recruited. Exposure-weighted scores for MetS during this 4-year period were calculated in two ways: cumulative number of MetS diagnoses (MetS exposure score, range: 0-4) and the composite of its five components (MetS component exposure score, range: 0-20). The multivariable Cox proportional-hazards model was used to assess CVD risk according to the exposure-weighted scores for MetS.
Results
MetS was identified at least once in 37.6% and persistent MetS in 8.2% of subjects. During the follow-up (median, 4.4 years), 10,522 cases of MI (0.4%) and 10,524 cases of stoke (0.4%) occurred. The risk of MI and stroke increased gradually with increasing exposure scores of MetS and its components (each P for trend < 0.0001). The hazard ratio [(HR) (95% CI)] of MI and stroke were 5.27 (4.20-6.62) and 3.90 (3.09-4.93), respectively, in those with a score of 20 compared with those with a MetS component exposure score of 0. People fulfilling only two MetS components out of 20 already had 22% increased risk of MI, and those with three MetS components had 24% increased risk of stroke. These associations were consistent in the subgroup and sensitivity analyses.
Conclusions
A dose-response relationship between the cumulative exposure to metabolic disturbances and incident MI or stroke was evident. Even minimal exposure to MetS components was sufficient to increase the risk of CVD significantly, highlighting the importance of intensive risk management for the prevention of CVD.



Cardiovasc Diabetol: 28 Sep 2020; 19:153
Lee EY, Han K, Kim DH, Park YM, ... Kim MK, Lee SH
Cardiovasc Diabetol: 28 Sep 2020; 19:153 | PMID: 32993664
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Abstract

Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study.

Lee DY, Han K, Park S, Yu JH, ... Park YG, Kim NH
Background
Previous research regarding long-term glucose variability over several years which is an emerging indicator of glycemic control in diabetes showed several limitations. We investigated whether variability in long-term fasting plasma glucose (FG) can predict the development of stroke, myocardial infarction (MI), and all-cause mortality in patients with diabetes.
Methods
This is a retrospective cohort study using the data provided by the Korean National Health Insurance Corporation. A total of 624,237 Koreans ≥ 20 years old with diabetes who had undergone health examinations at least twice from 2005 to 2008 and simultaneously more than once from 2009 to 2010 (baseline) without previous histories of stroke or MI. As a parameter of variability of FG, variability independent of mean (VIM) was calculated using FG levels measured at least three times during the 5 years until the baseline. Study endpoints were incident stroke, MI, and all-cause mortality through December 31, 2017.
Results
During follow-up, 25,038 cases of stroke, 15,832 cases of MI, and 44,716 deaths were identified. As the quartile of FG VIM increased, the risk of clinical outcomes serially increased after adjustment for confounding factors including duration and medications of diabetes and the mean FG. Adjusted hazard ratios (95% confidence intervals) of FG VIM quartile 4 compared with quartile 1 were 1.20 (1.16-1.24), 1.20 (1.15-1.25), and 1.32 (1.29-1.36) for stroke, MI and all-cause mortality, respectively. The impact of FG variability was higher in the elderly and those with a longer duration of diabetes and lower FG levels.
Conclusions
In diabetes, long-term glucose variability showed a dose-response relationship with the risk of stroke, MI, and all-cause mortality in this nationwide observational study.



Cardiovasc Diabetol: 21 Sep 2020; 19:144
Lee DY, Han K, Park S, Yu JH, ... Park YG, Kim NH
Cardiovasc Diabetol: 21 Sep 2020; 19:144 | PMID: 32962711
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Abstract

Arterial stiffness is an independent predictor for risk of mortality in patients with type 2 diabetes mellitus: the REBOUND study.

Kim JM, Kim SS, Kim IJ, Kim JH, ... Kim J,
Background
This study aimed to evaluate the benefit of brachial-ankle pulse wave velocity (baPWV) as a noninvasive marker of arterial stiffness for the prediction of all-cause and cause-specific mortality in patients with type 2 diabetes.
Methods
This multicenter prospective observational study analyzed 2308 patients with type 2 diabetes between 2008 and 2018. The patients were categorized according to the quartiles of baPWV. Cause of mortality was determined using death certificates and patient clinical records. We estimated proportional mortality rates from all causes, cardiovascular, cancer, and other causes among adults with diabetic status according to their baPWV. Cox regression models were used to estimate hazard ratios (HRs).
Results
There were 199 deaths (8.6%) in the study population during a median follow-up duration of 8.6 years. When baPWV was assessed as quartiles, a significantly higher risk of all-cause mortality (HR = 5.39, P < 0.001), cardiovascular-mortality (HR = 14.89, P < 0.001), cancer-mortality (HR = 5.42, P < 0.001), and other-cause mortality (HR = 4.12, P < 0.001) was found in quartile 4 (Q4, ≥ 1830 cm/s) than in quartiles 1-3 (Q1-3). Adding baPWV to baseline model containing conventional risk factors such as age, sex, diabetes duration, body mass index, glycated hemoglobin, systolic blood pressure, glomerular filtration rate, smoking, and insulin improved the risk prediction for all-cause (net reclassification index (NRI) = 49%, P < 0.001) and cause-specific (cardiovascular NRI = 28%, P = 0.030; cancer NRI = 55%, P < 0.001; other-cause NRI 51%, P < 0.001) mortality.
Conclusion
This long-term, large-scale, multicenter prospective observational cohort study provide evidence that increased arterial stiffness, as measured by baPWV, predicts the risk of all-cause and cause-specific mortality in type 2 diabetes, supporting the prognostic utility of baPWV. Trial registration Clinical Research Information Service (CRIS), KCT 0005010. Retrospectively Registered May 12, 2020. https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=16677.



Cardiovasc Diabetol: 21 Sep 2020; 19:143
Kim JM, Kim SS, Kim IJ, Kim JH, ... Kim J,
Cardiovasc Diabetol: 21 Sep 2020; 19:143 | PMID: 32962704
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Abstract

Association of glucose uptake of visceral fat and acute myocardial infarction: a pilot F-FDG PET/CT study.

Pahk K, Kim EJ, Joung C, Seo HS, Kim S
Background
Inflamed visceral adipose tissue (VAT) facilitates chronic inflammation in atherosclerotic lesions thereby leading to increased risk of coronary artery disease (CAD). In this study, we evaluated the glucose uptake of VAT and the carotid artery with F-fluorodeoxyglucose positron emission tomography (F-FDG PET/CT) and their association with CAD, including acute myocardial infarction (AMI).
Methods
A total of 90 participants were enrolled (32 with AMI, 33 with chronic stable angina; CSA, and 25 control participants) and undertook F-FDG PET/CT. VAT glucose uptake was measured by using maximum standardized uptake value (SUVmax) of VAT region. The target-to-background ratio (TBR) of carotid artery was defined as the SUVmax of carotid artery divided by the SUVmax of jugular vein. The SUVmax of spleen, bone-marrow (BM), and high-sensitivity C-reactive protein (hsCRP) were used for the assessment of systemic inflammatory activity.
Results
VAT SUVmax was highest in participants with AMI, intermediate in participants with CSA, and lowest in control participants. Carotid artery TBR and systemic inflammatory surrogate markers including spleen SUVmax, BM SUVmax, and hsCRP were also higher in the AMI group than in the CSA or control group. Furthermore, VAT SUVmax showed significant positive correlation with carotid artery TBR, spleen SUVmax, BM SUVmax, and hsCRP. In multivariate linear regression and logistic regression analyses, VAT SUVmax was independently associated with carotid artery TBR and AMI.
Conclusions
Glucose uptake of VAT assessed by F-FDG PET/CT was associated with the severity of CAD and synchronized with the carotid artery inflammation in participants with CAD.



Cardiovasc Diabetol: 23 Sep 2020; 19:145
Pahk K, Kim EJ, Joung C, Seo HS, Kim S
Cardiovasc Diabetol: 23 Sep 2020; 19:145 | PMID: 32972415
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Abstract

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.

Shimizu W, Kubota Y, Hoshika Y, Mozawa K, ... Tanabe J,
Background
Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity.
Methods
This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT.
Results
Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed.
Conclusions
This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events.
Trial registration
The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .



Cardiovasc Diabetol: 24 Sep 2020; 19:148
Shimizu W, Kubota Y, Hoshika Y, Mozawa K, ... Tanabe J,
Cardiovasc Diabetol: 24 Sep 2020; 19:148 | PMID: 32977831
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Abstract

Sortilin levels correlate with major cardiovascular events of diabetic patients with peripheral artery disease following revascularization: a prospective study.

Biscetti F, Nardella E, Rando MM, Cecchini AL, ... Landolfi R, Flex A
Background
Peripheral artery disease (PAD) represents one of the most relevant vascular complications of type 2 diabetes mellitus (T2DM). Moreover, T2DM patients suffering from PAD have an increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Sortilin, a protein involved in apolipoproteins trafficking, is associated with lower limb PAD in T2DM patients.
Objective
To evaluate the relationship between baseline serum levels of sortilin, MACE and MALE occurrence after revascularization of T2DM patients with PAD and chronic limb-threatening ischemia (CLTI).
Research design and methods
We performed a prospective non-randomized study including 230 statin-free T2DM patients with PAD and CLTI. Sortilin levels were measured before the endovascular intervention and incident outcomes were assessed during a 12 month follow-up.
Results
Sortilin levels were significantly increased in individuals with more aggressive PAD (2.25 ± 0.51 ng/mL vs 1.44 ± 0.47 ng/mL, p < 0.001). During follow-up, 83 MACE and 116 MALE occurred. In patients, who then developed MACE and MALE, sortilin was higher. In particular, 2.46 ± 0.53 ng/mL vs 1.55 ± 0.42 ng/mL, p < 0.001 for MACE and 2.10 ± 0.54 ng/mL vs 1.65 ± 0.65 ng/mL, p < 0.001 for MALE. After adjusting for traditional atherosclerosis risk factors, the association between sortilin and vascular outcomes remained significant in a multivariate analysis. In our receiver operating characteristics (ROC) curve analysis using sortilin levels the prediction of MACE incidence improved (area under the curve [AUC] = 0.94) and MALE (AUC = 0.72).
Conclusions
This study demonstrates that sortilin correlates with incidence of MACE and MALE after endovascular revascularization in a diabetic population with PAD and CLTI.



Cardiovasc Diabetol: 24 Sep 2020; 19:147
Biscetti F, Nardella E, Rando MM, Cecchini AL, ... Landolfi R, Flex A
Cardiovasc Diabetol: 24 Sep 2020; 19:147 | PMID: 32977814
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Impact:
Abstract

Impact of long-term glucose variability on coronary atherosclerosis progression in patients with type 2 diabetes: a 2.3 year follow-up study.

Li S, Tang X, Luo Y, Wu B, ... Liu J, Chen Y
Background
Glycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM).
Methods
A total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations [median 2.3 (1.8-3.1) years] were included. Fasting plasma glucose (FPG) was measured every 1-3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression.
Results
In the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm, and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV [CV-HbA1c: β = 0.241 (0.019-0.462), P = 0.034; CV-FPG β = 0.265 (0.060-0.465), P = 0.012], annual TPV progression [CV-HbA1c: β = 0.214 (0.023-0.405), P = 0.029; CV-FPG β = 0.218 (0.037-0.399), P = 0.019], and significant atherosclerosis progression [CV-HbA1c: odds ratio [OR] = 1.367 (1.149-1.650), P = 0.010; CV-FPG OR = 1.321 (1.127-1.634), P = 0.013].
Conclusions
Long-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM. Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered.



Cardiovasc Diabetol: 24 Sep 2020; 19:146
Li S, Tang X, Luo Y, Wu B, ... Liu J, Chen Y
Cardiovasc Diabetol: 24 Sep 2020; 19:146 | PMID: 32977802
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Impact:
Abstract

Long-term prognostic utility of low-density lipoprotein (LDL) triglyceride in real-world patients with coronary artery disease and diabetes or prediabetes.

Jin JL, Zhang HW, Cao YX, Liu HH, ... Santos R, Li JJ
Background
Recent guidelines highlighted the association between atherosclerosis and triglyceride-enriched lipoproteins in patients with impaired glucose metabolism. However, evidence from prospective studies for long-term prognostic utility of low-density lipoprotein triglyceride (LDL-TG) in real-world patients with prediabetes (Pre-DM) or diabetes mellitus (DM) and coronary artery disease (CAD) is currently not available. The aim of the present study was to evaluate the impact of LDL-TG on major adverse cardiovascular events (MACEs) in patients with stable CAD under different glucose metabolism status.
Methods
A total of 4381 patients with CAD were consecutively enrolled and plasma LDL-TG level was measured by an automated homogeneous assay. They were categorized according to both status of glucose metabolism [DM, Pre-DM, normal glycaemia regulation (NGR)] and tertiles of LDL-TG. All subjects were followed up for the occurrence of MACEs.
Results
During a median of 5.1 (interquartile range 3.9 to 5.9) years\' follow-up, 507 (11.6%) MACEs occurred. Cubic spline models showed a significant association between LDL-TG and MACEs in DM and Pre-DM but not in NGR. When the combined effect of elevated LDL-TG and glucose disorders was considered for risk stratification, the medium tertile of LDL-TG plus DM, and the highest tertile of LDL-TG plus Pre-DM or plus DM subgroups were associated with significantly higher risk of MACEs after adjustment of confounders including triglyceride [hazard ratios (95% confidence intervals): 1.843 (1.149-2.955), 1.828 (1.165-2.867), 2.212 (1.396-3.507), all p < 0.05]. Moreover, adding LDL-TG into the original model increased the C-statistic from 0.687 to 0.704 (∆C-statistic = 0.016, p = 0.028) and from 0.734 to 0.749 (∆C-statistic = 0.014, p = 0.002) in Pre-DM and DM, respectively.
Conclusions
In this longitudinal cohort study on real-world practice, higher LDL-TG was associated with worse outcomes among Pre-DM and DM patients with stable CAD.



Cardiovasc Diabetol: 26 Sep 2020; 19:152
Jin JL, Zhang HW, Cao YX, Liu HH, ... Santos R, Li JJ
Cardiovasc Diabetol: 26 Sep 2020; 19:152 | PMID: 32981521
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Impact:
Abstract

Diabetes as a risk factor for incident peripheral arterial disease in women compared to men: a systematic review and meta-analysis.

Chase-Vilchez AZ, Chan IHY, Peters SAE, Woodward M
Aims/hypothesis
Previous meta-analyses have suggested that diabetes confers a greater excess risk of coronary heart disease, stroke, vascular dementia, and heart failure in women compared to men. While the underlying mechanism that explains such greater excess risk is unknown, in the current meta-analysis we hypothesized that we would find a similar sex difference in the relationship between diabetes and peripheral arterial disease (PAD).
Methods
PubMed MEDLINE, the Cochrane Database of Systematic Reviews, and Embase were systematically searched for prospective population-based cohort studies, with no restriction on publication date, language, or country. We included studies that reported the relative risk (RR), and its variability, for incident PAD associated with diabetes in both sexes. We excluded studies that did not adjust at least for age, and in which participants had pre-existing PAD. In cases where sex-specific results were not reported, study authors were contacted. Random-effects meta-analyses with inverse variance weighting were used to obtain summary sex-specific RRs and the women: men ratio of RRs for PAD. The Newcastle-Ottawa scale was used to assess study quality.
Results
Data from seven cohorts, totalling 2071,260 participants (49.8% women), were included. The relative risk for incident PAD associated with diabetes compared with no diabetes was 1.96 (95% CI 1.29-2.63) in women and 1.84 (95% CI 1.29-2.86) in men, after adjusting for potential confounders. The multiple-adjusted RR ratio was 1.05 (95% CI 0.90-1.22), with virtually no heterogeneity between studies (I = 0%). All studies scored 6-8, on the Newcastle-Ottawa scale of 0-9, indicating good quality. Eleven of the 12 studies that met review inclusion criteria did not report sex-specific relative risk, and these data were collected through direct correspondence with the study authors.
Conclusion/interpretation
Consistent with other studies, we found evidence that diabetes is an independent risk factor for PAD. However, in contrast to similar studies of other types of cardiovascular disease, we did not find evidence that diabetes confers a greater excess risk in women compared to men for PAD. More research is needed to explain this sex differential between PAD and other forms of CVD, in the sequelae of diabetes. In addition, we found that very few studies reported the sex-specific relative risk for the association between diabetes and PAD, adding to existing evidence for the need for improved reporting of sex-disaggregated results in cardiovascular disease research.



Cardiovasc Diabetol: 25 Sep 2020; 19:151
Chase-Vilchez AZ, Chan IHY, Peters SAE, Woodward M
Cardiovasc Diabetol: 25 Sep 2020; 19:151 | PMID: 32979922
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Impact:
Abstract

Metformin may adversely affect orthostatic blood pressure recovery in patients with type 2 diabetes: substudy from the placebo-controlled Copenhagen Insulin and Metformin Therapy (CIMT) trial.

Hansen CS, Lundby-Christiansen L, Tarnow L, Gluud C, ... Jørgensen ME,
Background
Metformin has been shown to have both neuroprotective and neurodegenerative effects. The aim of this study was to investigate the effect of metformin in combination with insulin on cardiovascular autonomic neuropathy (CAN) and distal peripheral neuropathy (DPN) in individuals with type 2 diabetes (T2DM).
Methods
The study is a sub-study of the CIMT trial, a randomized placebo-controlled trial with a 2 × 3 factorial design, where 412 patients with T2DM were randomized to 18 months of metformin or placebo in addition to open-labelled insulin. Outcomes were measures of CAN: Changes in heart rate response to deep breathing (beat-to-beat), orthostatic blood pressure (OBP) and heart rate and vibration detection threshold (VDT) as a marker DPN. Serum levels of vitamin B12 and methyl malonic acid (MMA) were analysed.
Results
After 18 months early drop in OBP (30 s after standing) was increased in the metformin group compared to placebo: systolic blood pressure drop increased by 3.4 mmHg (95% CI 0.6; 6.2, p = 0.02) and diastolic blood pressure drop increased by 1.3 mmHg (95% CI 0.3; 2.6, p = 0.045) compared to placebo. Beat-to-beat variation decreased in the metformin group by 1.1 beats per minute (95% CI - 2.4; 0.2, p = 0.10). Metformin treatment did not affect VDT group difference - 0.33 V (95% CI - 1.99; 1.33, p = 0.39) or other outcomes. Changes in B12, MMA and HbA did not confound the associations.
Conclusions
Eighteen months of metformin treatment in combination with insulin compared with insulin alone increased early drop in OBP indicating an adverse effect of metformin on CAN independent of vitamin B12, MMA HbA. Trial registration The protocol was approved by the Regional Committee on Biomedical Research Ethics (H-D-2007-112), the Danish Medicines Agency and registered with ClinicalTrials.gov (NCT00657943).



Cardiovasc Diabetol: 25 Sep 2020; 19:150
Hansen CS, Lundby-Christiansen L, Tarnow L, Gluud C, ... Jørgensen ME,
Cardiovasc Diabetol: 25 Sep 2020; 19:150 | PMID: 32979921
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Impact:
Abstract

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet.

Yoshida M, Nakamura K, Miyoshi T, Yoshida M, ... Miura D, Ito H
Background
Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.
Methods
Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.
Results
After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.
Conclusions
Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.



Cardiovasc Diabetol: 25 Sep 2020; 19:149
Yoshida M, Nakamura K, Miyoshi T, Yoshida M, ... Miura D, Ito H
Cardiovasc Diabetol: 25 Sep 2020; 19:149 | PMID: 32979918
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Impact:
Abstract

Heterogeneity of antidiabetic treatment effect on the risk of major adverse cardiovascular events in type 2 diabetes: a systematic review and meta-analysis.

D\'Andrea E, Kesselheim AS, Franklin JM, Jung EH, Hey SP, Patorno E
Background
We explored whether clinically relevant baseline characteristics of patients with type 2 diabetes can modify the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on the risk of major adverse cardiovascular events (MACE).
Methods
We investigated Medline and EMBASE through June 2019. We included randomized clinical trials reporting the effect of GLP-1 RA or SGLT-2i on MACE in subgroups of patients with type 2 diabetes, identified through key baseline factors: established cardiovascular disease; heart failure; chronic kidney disease; uncontrolled diabetes; duration of diabetes; hypertension; obesity; age; gender and race. Hazard ratios (HRs) and 95% confidence intervals (CIs) from trials were meta-analyzed using random-effects models.
Results
Ten trials enrolling 89,790 patients were included in the analyses. Subgroup meta-analyses showed a 14% risk reduction of MACE in patients with established cardiovascular disease [GLP1-RA: HR, 0.86 (95% CI, 0.80-0.93); SGLT-2i: 0.86 (0.80-0.93)], and no effect in at-risk patients without history of cardiovascular events [GLP1-RA: 0.94 (0.82-1.07); SGLT-2i: 1.00 (0.87-1.16)]. We observed a trend toward larger treatment benefits with SGLT-2i among patients with chronic kidney disease [0.82 (0.69-0.97)], and patients with uncontrolled diabetes for both GLP1-RA or SGLT-2i [GLP1-RA: 0.82 (0.71-0.95); SGLT-2i: 0.84 (0.75-0.95)]. Uncontrolled hypertension, obesity, gender, age and race did not appear to modify the effect of these drugs.
Conclusions
In this exploratory analysis, history of cardiovascular disease appeared to modify the treatment effect of SGLT2i or GLP1-RA on MACE. Chronic kidney disease and uncontrolled diabetes should be further investigated as potential effect modifiers.



Cardiovasc Diabetol: 28 Sep 2020; 19:154
D'Andrea E, Kesselheim AS, Franklin JM, Jung EH, Hey SP, Patorno E
Cardiovasc Diabetol: 28 Sep 2020; 19:154 | PMID: 32993654
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Impact:
Abstract

The impact of triglyceride-glucose index on incident cardiovascular events during 16 years of follow-up: Tehran Lipid and Glucose Study.

Barzegar N, Tohidi M, Hasheminia M, Azizi F, Hadaegh F
Background
To investigate whether the Triglyceride-Glucose index (TyG-index) is associated with increased risk of cardiovascular diseases (CVD)/coronary heart disease (CHD).
Methods
A total of 7521 Iranians aged ≥ 30 years (male = 3367) were included in the study. Multivariate Cox regression analyses (adjusted for age, gender, waist circumference, body mass index, educational level, smoking status, physical activity, family history of CVD, type 2 diabetes, hypertension, low and high density lipoprotein cholesterol, and lipid lowering drugs) were used to assess the risk of incident CVD/CHD across quintiles and for 1-standard deviation (SD) increase in the TyG-index. The cut off point for TyG-index was assessed by the minimum value of [Formula: see text]. We also examined the added value of the TyG-index in addition to the Framingham risk score when predicting CVD.
Results
During follow-up, 1084 cases of CVD (male = 634) were recorded. We found a significant trend of TyG-index for incident CVD/CHD in multivariate analysis (both Ps for tend ≤ 0.002). Moreover, a 1-SD increase in TyG-index was associated with significant risk of CVD/CHD in multivariate analysis [1.16 (1.07-1.25) and 1.19 (1.10-1.29), respectively]. The cut-off value of TyG-index for incident CVD was 9.03 (59.2% sensitivity and 63.2% specificity); the corresponding value of TyG-index for incident CHD was 9.03 (60.0% sensitivity and 62.8% specificity), respectively. Although no interaction was found between gender and TyG-index for CVD/CHD in multivariate analysis (both Ps for interaction > 0.085), the significant trend of TyG-index was observed only among females for incident CVD (P = 0.035). A significant interaction was found between age groups (i.e. ≥ 60 vs < 60 years) and TyG-index for CVD outcomes in the multivariate model (P-value for interaction = 0.046). Accordingly, a significant association between the TyG-index and outcomes was found only among the younger age group. Among the population aged < 60 the addition of TyG-index to the Framingham risk score (FRS) did not show improvement in the predictive ability of the FRS, using integrated discrimination improvement.
Conclusion
The TyG-index is significantly associated with increased risk of CVD/CHD incidence; this issue was more prominent among the younger population. However, adding TyG-index to FRS does not provide better risk prediction for CVD.



Cardiovasc Diabetol: 28 Sep 2020; 19:155
Barzegar N, Tohidi M, Hasheminia M, Azizi F, Hadaegh F
Cardiovasc Diabetol: 28 Sep 2020; 19:155 | PMID: 32993633
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Impact:
Abstract

Fibroblast growth factor-23 is associated with imaging markers of diabetic cardiomyopathy and anti-diabetic therapeutics.

Sørensen MH, Bojer AS, Jørgensen NR, Broadbent DA, ... Madsen PL, Gæde P
Background
The biomarker fibroblast growth factor-23 (FGF-23) has been associated with increased cardiovascular morbidity and mortality in both patients with and without type 2 diabetes. The aim of this study was to evaluate the relationship between FGF-23 and cardiac structure, function and perfusion in patients with type 2 diabetes and normal or mildly impaired kidney function. Furthermore, to investigate the association between FGF-23, anti-diabetes therapy and the classic complications and risk factors associated with type 2 diabetes.
Methods
In this cross-sectional study, 246 patients with type 2 diabetes underwent echocardiography and advanced cardiac magnetic resonance imaging to assess left ventricular (LV) structure and function. In addition, myocardial blood flow (MBF) during rest and pharmacological stress (adenosine 140 µg/kg/min) were evaluated in 183 of the patients. Patients with eGFR < 60 ml/min/1.73 m were excluded.
Results
Median (Q1-Q3) FGF-23 was 74 (58-91) ng/L. Patients with FGF-23 above the median had lower MBF during stress (2.3 ± 0.9 vs. 2.7 ± 0.9 ml/min/g, P = 0.001) and lower overall myocardial perfusion reserve (MPR) (2.7 ± 0.8 vs. 3.3 ± 1.1, P < 0.001). LV mass (143 ± 40 vs. 138 ± 36 g, P = 0.04) and E/e* (8.5 ± 3.2 vs. 7.6 ± 2.7, P = 0.04) were higher in patients with FGF-23 above the median. In a linear model adjusted for age, sex, eGFR and hypertension, increasing FGF-23 was associated with decreased MPR (P < 0.01, R = 0.11) and increased E/e* (P < 0.01, R = 0.07). FGF-23 was lower in patients receiving glucagon like peptide-1 (GLP-1) analogues (71 (57-86) vs. 80 (60-98) ng/L, P = 0.01) than in those who did not receive GLP-1 analogues.
Conclusions
In patients with type 2 diabetes and normal or mildly impaired kidney function, increased levels of FGF-23 are associated with impaired cardiac diastolic function and decreased MPR, caused by a decrease in maximal MBF during stress. Use of GLP-1 analogues is associated with decreased levels of FGF-23. Clinical trial registration https://www.clinicaltrials.gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016.



Cardiovasc Diabetol: 29 Sep 2020; 19:158
Sørensen MH, Bojer AS, Jørgensen NR, Broadbent DA, ... Madsen PL, Gæde P
Cardiovasc Diabetol: 29 Sep 2020; 19:158 | PMID: 32998751
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Impact:
Abstract

Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure.

Sayour AA, Oláh A, Ruppert M, Barta BA, ... Merkely B, Radovits T
Background
Whereas selective sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently showed cardiovascular protective effects in large outcome trials independent of the presence of type 2 diabetes mellitus (T2DM), the cardiovascular effects of dual SGLT1/2 inhibitors remain to be elucidated. Despite its clinical relevance, data are scarce regarding left ventricular (LV) SGLT1 expression in distinct heart failure (HF) pathologies. We aimed to characterize LV SGLT1 expression in human patients with end-stage HF, in context of the other two major glucose transporters: GLUT1 and GLUT4.
Methods
Control LV samples (Control, n = 9) were harvested from patients with preserved LV systolic function who went through mitral valve replacement. LV samples from HF patients undergoing heart transplantation (n = 71) were obtained according to the following etiological subgroups: hypertrophic cardiomyopathy (HCM, n = 7); idiopathic dilated cardiomyopathy (DCM, n = 12); ischemic heart disease without T2DM (IHD, n = 14), IHD with T2DM (IHD + T2DM, n = 11); and HF patients with cardiac resynchronization therapy (DCM:CRT, n = 9, IHD:CRT, n = 9 and IHD-T2DM:CRT, n = 9). We measured LV SGLT1, GLUT1 and GLUT4 gene expressions with qRT-PCR. The protein expression of SGLT1, and activating phosphorylation of AMP-activated protein kinase (AMPKα) and extracellular signal-regulated kinase 1/2 (ERK1/2) were quantified by western blotting. Immunohistochemical staining of SGLT1 was performed.
Results
Compared with controls, LV SGLT1 mRNA and protein expressions were significantly and comparably upregulated in HF patients with DCM, IHD and IHD + T2DM (all P < 0.05), but not in HCM. LV SGLT1 mRNA and protein expressions positively correlated with LVEDD and negatively correlated with EF (all P < 0.01). Whereas AMPKα phosphorylation was positively associated with SGLT1 protein expression, ERK1/2 phosphorylation showed a negative correlation (both P < 0.01). Immunohistochemical staining revealed that SGLT1 expression was predominantly confined to cardiomyocytes, and not fibrotic tissue. Overall, CRT was associated with reduction of LV SGLT1 expression, especially in patients with DCM.
Conclusions
Myocardial LV SGLT1 is upregulated in patients with HF (except in those with HCM), correlates significantly with parameters of cardiac remodeling (LVEDD) and systolic function (EF), and is downregulated in DCM patients with CRT. The possible role of SGLT1 in LV remodeling needs to be elucidated.



Cardiovasc Diabetol: 29 Sep 2020; 19:159
Sayour AA, Oláh A, Ruppert M, Barta BA, ... Merkely B, Radovits T
Cardiovasc Diabetol: 29 Sep 2020; 19:159 | PMID: 32998746
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Impact:
Abstract

The additive effects of type 2 diabetes mellitus on left ventricular deformation and myocardial perfusion in essential hypertension: a 3.0 T cardiac magnetic resonance study.

Li XM, Jiang L, Guo YK, Ren Y, ... Yan WF, Yang ZG
Background
Type 2 diabetes mellitus (T2DM) increases the risks of heart failure and mortality in patients with hypertension, however the underlying mechanism is unclear. This study aims to investigate the impact of coexisting T2DM on left ventricular (LV) deformation and myocardial perfusion in hypertensive individuals.
Materials and methods
Seventy hypertensive patients without T2DM [HTN(T2DM-)], forty patients with T2DM [HTN(T2DM+)] and 37 age- and sex-matched controls underwent cardiac magnetic resonance examination. Left ventricular (LV) myocardial strains, including global radial (GRPS), circumferential (GCPS) and longitudinal peak strain (GLPS), and resting myocardial perfusion indices, including upslope, time to maximum signal intensity (TTM), and max signal intensity (MaxSI), were measured and compared among groups by analysis of covariance after adjusting for age, sex, body mass index (BMI) and heart rate followed by Bonferroni\'s post hoc test. Backwards stepwise multivariable linear regression analyses were performed to determine the effects of T2DM on LV strains and myocardial perfusion indices in patients with hypertension.
Results
Both GRPS and GLPS deteriorated significantly from controls, through HTN(T2DM-), to HTN(T2DM+) group; GCPS in HTN(T2DM+) group was lower than those in both HTN(T2DM-) and control groups. Compared with controls, HTN(T2DM-) group showed higher myocardial perfusion, and HTN(T2DM+) group exhibited lower perfusion than HTN(T2DM-) group and controls. Multiple regression analyses considering covariates of systolic blood pressure, age, sex, BMI, heart rate, smoking, indexed LV mass and eGFR demonstrated that T2DM was independently associated with LV strains (GRPS: p = 0.002, model R= 0.383; GCPS: p < 0.001, model R= 0.472; and GLPS: p = 0.002, model R= 0.424, respectively) and perfusion indices (upslope: p < 0.001, model R= 0.293; TTM: p < 0.001, model R= 0.299; and MaxSI: p < 0.001, model R= 0.268, respectively) in hypertension. When both T2DM and perfusion indices were included in the regression analyses, both T2DM and TTM were independently associated with GRPS (p = 0.044 and 0.017, model R= 0.390) and GCPS (p = 0.002 and 0.001, model R= 0.424), and T2DM but not perfusion indices was independently associated with GLPS (p = 0.002, model R= 0.424).
Conclusion
In patients with hypertension, T2DM had an additive deleterious effect on subclinical LV systolic dysfunction and myocardial perfusion, and impaired myocardial perfusion by coexisting T2DM was associated with deteriorated LV systolic dysfunction.



Cardiovasc Diabetol: 29 Sep 2020; 19:161
Li XM, Jiang L, Guo YK, Ren Y, ... Yan WF, Yang ZG
Cardiovasc Diabetol: 29 Sep 2020; 19:161 | PMID: 32998742
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Impact:
Abstract

Chronic kidney disease and undiagnosed atrial fibrillation in individuals with diabetes.

Heo NJ, Rhee SY, Waalen J, Steinhubl S
Background
Diabetes is an independent risk factor for atrial fibrillation (AF), which is associated with increases in mortality and morbidity, as well as a diminished quality of life. Renal involvement in diabetes is common, and since chronic kidney disease (CKD) shares several of the same putative mechanisms as AF, it may contribute to its increased risk in individuals with diabetes. The objective of this study is to identify the relationship between CKD and the rates of newly-diagnosed AF in individuals with diabetes taking part in a screening program using a self-applied wearable electrocardiogram (ECG) patch.
Materials and methods
The study included 608 individuals with a diagnosis of diabetes among 1738 total actively monitored participants in the prospective mHealth Screening to Prevent Strokes (mSToPS) trial. Participants, without a prior diagnosis of AF, wore an ECG patch for 2 weeks, twice, over a 4-months period and followed clinically through claims data for 1 year. Definitions of CKD included ICD-9 or ICD-10 chronic renal failure diagnostic codes, and the Health Profile Database algorithm. Individuals requiring dialysis were excluded from trial enrollment.
Results
Ninety-six (15.8%) of study participants with diabetes also had a diagnosis of CKD. Over 12 months of follow-up, 19 new cases of AF were detected among the 608 participants. AF was newly diagnosed in 7.3% of participants with CKD and 2.3% in those without (P < 0.05) over 12 months of follow-up. In a univariate Cox proportional hazard regression analysis, the risk of incident AF was 3 times higher in individuals with CKD relative to those without CKD: hazard ratios (HR) 3.106 (95% CI 1.2-7.9). After adjusting for the effect of age, sex, and hypertension, the risk of incident AF was still significantly higher in those with CKD: HR 2.886 (95% CI 1.1-7.5).
Conclusion
Among individuals with diabetes, CKD significantly increases the risk of incident AF. Identification of AF prior to clinical symptoms through active ECG screening could help to improve the clinical outcomes in individuals with CKD and diabetes.



Cardiovasc Diabetol: 29 Sep 2020; 19:157
Heo NJ, Rhee SY, Waalen J, Steinhubl S
Cardiovasc Diabetol: 29 Sep 2020; 19:157 | PMID: 32998739
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Impact:
Abstract

Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor.

Lee HF, Chen SW, Liu JR, Li PR, ... Chan YH, See LC
Background
Whether sodium glucose co-transporter 2 inhibitors (SGLT2i) are associated with a lower risk of cardiovascular as well as adverse lower limb events in patients with type-2 diabetes mellitus (T2DM) and concomitant peripheral artery disease (PAD) is unclear. We aimed to evaluate the risk of cardiovascular and limb events, and death associated with the use of SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) among a longitudinal and national cohort of patients with T2DM.
Methods
In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, we identified a total of 11,431 and 93,972 consecutive T2DM patients with PAD taking SGLT2i and DPP4i, respectively, from May 1, 2016, to December 31, 2017. We used 1:1 propensity score matching (PSM) to balance covariates across study groups. Patients were followed from the drug index date until the occurrence of clinical outcomes, death, discontinuation of the index drug, or the end of the study period, whichever occurred first.
Results
Overall, 56% and 44% of the patients were treated with dapagliflozin and empagliflozin, respectively. The use of SGLT2i had comparable risks of ischemic stroke and acute myocardial infarction, and was associated with lower risks of congestive heart failure (CHF) [hazard ratio (HR): 0.66; 95% confidence interval (CI) 0.49-0.89; p = 0.0062], lower limb ischemia requiring revascularization (HR: 0.73; 95% CI 0.54-0.98; p = 0.0367) or amputation (HR: 0.43; 95% CI 0.30-0.62; p < 0.0001), and cardiovascular death (HR: 0.67; 95% CI 0.49-0.90; p = 0.0089) when compared with the DDP4i group after PSM. The subgroup analysis revealed consistent results for CHF and major adverse limb outcomes for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of chronic kidney disease and established cardiovascular disease was consistent with the main analysis.
Conclusions
SGLT2i were associated with lower risks of CHF and adverse lower limb events compared with DPP4i among patients with T2DM and PAD in real-world practice.



Cardiovasc Diabetol: 29 Sep 2020; 19:160
Lee HF, Chen SW, Liu JR, Li PR, ... Chan YH, See LC
Cardiovasc Diabetol: 29 Sep 2020; 19:160 | PMID: 32998736
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Impact:
Abstract

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials.

Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I
Background
Semaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. semaglutide and 0.79 [0.57;1.11] for once-daily oral semaglutide). However, there is little evidence for an effect of semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of semaglutide in subjects across a continuum of baseline CV risk.
Methods
Data from the s.c. (SUSTAIN) and oral (PIONEER) semaglutide phase 3a clinical trial programs were combined according to randomized treatment (semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model.
Results
The CV risk prediction model performed satisfactorily when applied to the semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included.
Conclusion
Semaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.



Cardiovasc Diabetol: 29 Sep 2020; 19:156
Husain M, Bain SC, Holst AG, Mark T, Rasmussen S, Lingvay I
Cardiovasc Diabetol: 29 Sep 2020; 19:156 | PMID: 32998732
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Impact:
Abstract

Left atrial strain and diastolic function abnormalities in obese and type 2 diabetic adolescents and young adults.

Steele JM, Urbina EM, Mazur WM, Khoury PR, ... Tretter JT, Alsaied T
Background
Adults with obesity and type 2 diabetes mellitus (T2DM) related to obesity are at increased risk of heart failure with preserved ejection fraction (HFpEF). Whether left ventricular (LV) diastolic function abnormalities related to obesity and T2DM start in adolescence and early adulthood is unknown. We non-invasively evaluated the differences seen in LV diastolic and left atrial (LA) function in adolescents and young adults with obesity and T2DM.
Methods
We analyzed echocardiographic measures of LV diastolic function in patients with structurally normal hearts which were divided into 3 groups (normal weight, obese, and T2DM). Spectral and tissue Doppler and 2-D speckle tracking measurements of diastolic function were obtained. Logistic regression was performed to compare the prevalence of abnormalities in diastolic function based on the worst 25th percentile for each measure to determine the prevalence of diastolic and LA function abnormalities in obese and T2DM patients.
Results
331 teenagers and young adults (median age 22.1 years) were analyzed (101 normal weight, 114 obese, 116 T2DM). Obese and T2DM group had lower E/A and higher E/e\'. Obese and T2DM patients had significantly lower atrial reservoir, conduit, and booster strain and worse reservoir and conduit strain rate compared to normal patients (p < 0.001 for all measures). All patients had normal LA volumes. On multivariable analysis, conduit strain and reservoir and conduit strain rate were independently associated with having below the 25th percentile e\'. Conduit strain rate was independently associated with having below the 25th percentile for mitral E/A ratio on multivariable analysis.
Conclusions
Abnormal indices of LV diastolic function are detected in adolescents and young adults with obesity and T2DM. LA function and strain analysis were able to detect evidence of decreased reservoir, conduit, and booster strain in these patients although LA volume was normal. The use of LA function strain may increase our ability to detect early diastolic function abnormalities in this population.



Cardiovasc Diabetol: 30 Sep 2020; 19:163
Steele JM, Urbina EM, Mazur WM, Khoury PR, ... Tretter JT, Alsaied T
Cardiovasc Diabetol: 30 Sep 2020; 19:163 | PMID: 33004030
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Impact:
Abstract

Clinical outcome of biodegradable polymer sirolimus-eluting stent and durable polymer everolimus-eluting stent in patients with diabetes.

Kakizaki R, Minami Y, Katamine M, Katsura A, ... Shimohama T, Ako J
Background
Diabetes mellitus is a risk for increased incidence of adverse clinical events after percutaneous coronary intervention. However, the difference in the incidence of adverse clinical events according to stent type in patients with diabetes remains to be elucidated. In the present study, we aimed to compare the clinical outcomes between patients treated with the biodegradable polymer sirolimus-eluting stents (BP-SES) and the durable polymer everolimus-eluting stents (DP-EES) among patients with diabetes.
Methods
Among 631 lesions in 510 consecutive patients treated with either BP-SES or DP-EES, 165 lesions in 141 patients with diabetes mellitus and stable angina pectoris were identified and classified into the BP-SES group (48 lesions in 44 patients) and the DP-EES group (117 lesions in 100 patients). The incidence of adverse clinical events after stent implantation was compared between the 2 groups.
Results
There was no significant difference in the prevalence of conventional risk factors, lesion characteristics, and procedural characteristics between the 2 groups. During median 386 [334-472] days follow-up, the incidence of target lesion revascularization (11.4 vs. 2.0%, p = 0.003) and device-oriented clinical endpoint (13.6 vs. 6.0%, p = 0.035) in the BP-SES group was significantly greater than that in the DP-EES group. A univariate model demonstrated that the BP-SES usage was significantly associated with the higher incidence of target lesion revascularization (odds ratio, 6.686; 95% confidence interval, 1.234-36.217; p = 0.028).
Conclusion
BP-SES was associated with the greater incidence of TLR than the DP-EES in patients with diabetes mellitus. Further studies with larger cohorts and longer follow-up are required to confirm the present results.



Cardiovasc Diabetol: 30 Sep 2020; 19:162
Kakizaki R, Minami Y, Katamine M, Katsura A, ... Shimohama T, Ako J
Cardiovasc Diabetol: 30 Sep 2020; 19:162 | PMID: 33004019
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Impact:
Abstract

Comparative effectiveness of dulaglutide versus liraglutide in Asian type 2 diabetes patients: a multi-institutional cohort study and meta-analysis.

Chang KC, Shao SC, Kuo S, Yang CY, ... Chan YY, Ou HT
Background
Head-to-head comparison of clinical effectiveness between dulaglutide and liraglutide in Asia is limited. This study was aimed to assess the real-world comparative effectiveness of dulaglutide versus liraglutide.
Methods
We conducted a retrospective cohort study by utilizing multi-institutional electronic medical records to identify real-world type 2 diabetes patients treated with dulaglutide or liraglutide during 2016-2018 in Taiwan and followed up until 2019. Effectiveness outcomes were assessed at every 3 months in the 1-year follow-up. Propensity score techniques were applied to enhance between-group comparability. Significant differences in changes of effectiveness outcomes between treatment groups during the follow-up were examined and further analyzed using mixed-model repeated-measures approaches.
Results
A total of 1512 subjects receiving dulaglutide and 1513 subjects receiving liraglutide were identified. At 12 months, significant HbA1c changes from baseline were found in both treatments (dulaglutide: - 1.06%, p < 0.001; liraglutide: - 0.83%, p < 0.001), with a significant between-group difference (- 0.23%, 95% confidence interval - 0.38 to - 0.08%, p < 0.01). Both treatments yielded significant declines in weight, alanine aminotransferase level, and estimated glomerular filtration rate from baseline (dulaglutide: - 1.14 kg, - 3.08 U/L and - 2.08 mL/min/1.73 m, p < 0.01; liraglutide: - 1.64 kg, - 3.65 U/L and - 2.33 mL/min/1.73 m, p < 0.001), whereas only dulaglutide yielded a significant systolic blood pressure reduction (- 2.47 mmHg, p < 0.001). Between-group differences in changes of weight, blood pressure, and liver and renal functions at 12 months were not statistically significant.
Conclusions
In real-world T2D patients, dulaglutide versus liraglutide was associated with better glycemic control and comparable effects on changes of weight, blood pressure, and liver and renal functions.



Cardiovasc Diabetol: 08 Oct 2020; 19:172
Chang KC, Shao SC, Kuo S, Yang CY, ... Chan YY, Ou HT
Cardiovasc Diabetol: 08 Oct 2020; 19:172 | PMID: 33036617
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Impact:
Abstract

Cardiovascular risks and bleeding with non-vitamin K antagonist oral anticoagulant versus warfarin in patients with type 2 diabetes: a tapered matching cohort study.

Yu D, Zhao Z, Simmons D
Background
We compared the risk of bleeding and cardiovascular disease (CVD) events between non-vitamin K antagonist oral anticoagulant (NOAC) and warfarin in people with type 2 diabetes (T2DM).
Methods
862 Incident NOAC users and 626 incident warfarin users with T2DM were identified from within 40 UK general practice (1/4/2017-30/9/2018). Outcomes included incident hospitalisation for bleeding, CVD and re-hospitalisation for CVD within 12 months since first anticoagulant prescription, identified from linked hospitalisation data. A tapered matching method was applied to form comparison cohorts: coarsened exact matching restricted the comparison to areas of sufficient overlap in missingness and characteristics: (i) demographic characteristics; (ii) clinical measurements; (iii) prior bleeding and CVD history; (iv) prescriptions with bleeding; (v) anti-hypertensive treatment(s); (vi) anti-diabetes treatment(s). Entropy balancing sequentially balanced NOAC and warfarin users on their distribution of (i-vi). Weighted logistic regression modelling estimated outcome odds ratios (ORs), using entropy balancing weights from steps i-vi.
Results
The 12-month ORs of bleeding with NOAC (n = 582) vs matched/balanced warfarin (n = 486) were 1.93 (95% confidence interval 0.97-3.84), 2.14 (1.03-4.44), 2.31 (1.10-4.85), 2.42 (1.14-5.14), 2.41 (1.12-5.18), and 2.51 (1.17-5.38) through steps i-vi. ORs for CVD re-hospitalisation was increased with NOAC treatment through steps i-vi: 2.21 (1.04-4.68), 2.13 (1.01-4.52), 2.47 (1.08-5.62), 2.46 (1.02-5.94), 2.51 (1.01-6.20), and 2.66 (1.02-6.94).
Conclusions
Incident NOAC use among T2DM is associated with increased risk of bleeding hospitalisation and CVD re-hospitalisation compared with incident warfarin use. For T2DM, caution is required in prescribing NOACs as first anticoagulant treatment. Further large-scale replication studies in external datasets are warranted.



Cardiovasc Diabetol: 09 Oct 2020; 19:174
Yu D, Zhao Z, Simmons D
Cardiovasc Diabetol: 09 Oct 2020; 19:174 | PMID: 33038936
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Impact:
Abstract

Everolimus-eluting bioresorbable scaffolds and metallic stents in diabetic patients: a patient-level pooled analysis of the prospective ABSORB DM Benelux Study, TWENTE and DUTCH PEERS.

Hommels TM, Hermanides RS, Berta B, Fabris E, ... von Birgelen C, Kedhi E
Background
Several studies compared everolimus-eluting bioresorbable scaffolds (EE-BRS) with everolimus-eluting stents (EES), but only few assessed these devices in patients with diabetes mellitus.
Aim
To evaluate the safety and efficacy outcomes of all-comer patients with diabetes mellitus up to 2 years after treatment with EE-BRS or EES.
Methods
We performed a post hoc pooled analysis of patient-level data in diabetic patients who were treated with EE-BRS or EES in 3 prospective clinical trials: The ABSORB DM Benelux Study (NTR5447), TWENTE (NTR1256/NCT01066650) and DUTCH PEERS (NTR2413/NCT01331707). Primary endpoint of the analysis was target lesion failure (TLF): a composite of cardiac death, target vessel myocardial infarction or clinically driven target lesion revascularization. Secondary endpoints included major adverse cardiac events (MACE): a composite of all-cause death, any myocardial infarction or clinically driven target vessel revascularization, as well as definite or probable device thrombosis (ST).
Results
A total of 499 diabetic patients were assessed, of whom 150 received EE-BRS and 249 received EES. Total available follow-up was 222.6 patient years (PY) in the EE-BRS and 464.9 PY in the EES group. The adverse events rates were similar in both treatment groups for TLF (7.2 vs. 5.2 events per 100 PY, p = 0.39; adjusted hazard ratio (HR) = 1.48 (95% confidence interval (CI): 0.77-2.87), p = 0.24), MACE (9.1 vs. 8.3 per 100 PY, p = 0.83; adjusted HR = 1.23 (95% CI: 0.70-2.17), p = 0.47), and ST (0.9 vs. 0.6 per 100 PY, p > 0.99).
Conclusion
In this patient-level pooled analysis of patients with diabetes mellitus from 3 clinical trials, EE-BRS showed clinical outcomes that were quite similar to EES.



Cardiovasc Diabetol: 01 Oct 2020; 19:165
Hommels TM, Hermanides RS, Berta B, Fabris E, ... von Birgelen C, Kedhi E
Cardiovasc Diabetol: 01 Oct 2020; 19:165 | PMID: 33008407
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Impact:
Abstract

Evaluation of cardiovascular risk in adults with type 1 diabetes: poor concordance between the 2019 ESC risk classification and 10-year cardiovascular risk prediction according to the Steno Type 1 Risk Engine.

Tecce N, Masulli M, Lupoli R, Della Pepa G, ... Riccardi G, Capaldo B
Background
Patients with type 1 diabetes (T1D) have higher mortality risk compared to the general population; this is largely due to increased rates of cardiovascular disease (CVD). As accurate CVD risk stratification is essential for an appropriate preventive strategy, we aimed to evaluate the concordance between 2019 European Society of Cardiology (ESC) CVD risk classification and the 10-year CVD risk prediction according to the Steno Type 1 Risk Engine (ST1RE) in adults with T1D.
Methods
A cohort of 575 adults with T1D (272F/303M, mean age 36 ± 12 years) were studied. Patients were stratified in different CVD risk categories according to ESC criteria and the 10-year CVD risk prediction was estimated with ST1RE within each category.
Results
Men had higher BMI, WC, SBP than women, while no difference was found in HbA1c levels between genders. According to the ESC classification, 92.5% of patients aged < 35 years and 100% of patients ≥ 35 years were at very high/high risk. Conversely, using ST1RE to predict the 10-year CVD risk within each ESC category, among patients at very high risk according to ESC, almost all (99%) had a moderate CVD risk according to ST1RE if age < 35 years; among patients aged ≥35 years, the majority (59.1%) was at moderate risk and only 12% had a predicted very high risk by ST1RE. The presence of target organ damage or three o more CV risk factors, or early onset T1D of long duration (> 20 years) alone identified few patients (< 30%) among those aged ≥35 years, who were at very high risk according to ESC, in whom this condition was confirmed by ST1RE; conversely, the coexistence of two or more of these criteria identified about half of the patients at high/very high risk also according to this predicting algorithm. When only patients aged ≥ 50 years were considered, there was greater concordance between ESC classification and ST1RE prediction, since as many as 78% of those at high/very high risk according to ESC were confirmed as such also by ST1RE.
Conclusions
Using ESC criteria, a large proportion (45%) of T1D patients without CVD are classified at very high CVD risk; however, among them, none of those < 35 years and only 12% of those ≥ 35 years could be confirmed at very high CVD risk by the ST1RE predicting algorithm. More studies are needed to characterize the clinical and metabolic features of T1D patients that identify those at very high CVD risk, in whom a very aggressive cardioprotective treatment would be justified.



Cardiovasc Diabetol: 02 Oct 2020; 19:166
Tecce N, Masulli M, Lupoli R, Della Pepa G, ... Riccardi G, Capaldo B
Cardiovasc Diabetol: 02 Oct 2020; 19:166 | PMID: 33010807
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Impact:
Abstract

Association of circulating PCSK9 concentration with cardiovascular metabolic markers and outcomes in stable coronary artery disease patients with or without diabetes: a prospective, observational cohort study.

Peng J, Liu MM, Jin JL, Cao YX, ... Xu RX, Li JJ
Background
Whether plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels is a predictor for cardiovascular outcomes has currently been controversial. No data is currently available regarding the relation of PCSK9 to cardiovascular metabolic markers (CVMMs) and major adverse cardiovascular events (MACEs) in stable coronary artery disease (CAD) patients with diabetes or without diabetes.
Methods
A total 1225 untreated patients with stable CAD were consecutively enrolled and their baseline plasma PCSK9 levels were determined by ELISA. Patients were divided into high and low PCSK9 groups according to PCSK9 median. All patients followed up for the occurrence of MACEs and received standard therapy after admission. The associations of PCSK9 with CVMMs and MACEs were evaluated.
Results
PCSK9 levels were positively correlated with multiple CVMMs including total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and hemoglobin A at baseline (all p < 0.05). During a median follow-up of 3.3 years, 103 (8.4%) events occurred. PCSK9 levels were higher in patients with events compared to those without (p < 0.05). The Kaplan-Meier analysis displayed that patients in high PCSK9 group had lower event-free survival than that in low group (p < 0.05). Multivariable Cox regression analysis revealed that PCSK9 levels were independently associated with MACEs in diabetic patients (adjusted hazard ratio [HR]: 1.361, 95% confidence interval [CI]: 1.037-1.785, p < 0.05). When added the combination of PCSK9 levels and diabetic status to stratifying factors, patients in high PCSK9 group appeared to have extremely high risk of subsequent MACEs with diabetes (adjusted HR: 5.233, 95% CI: 2.546-10.757, p < 0.01).
Conclusions
The present study firstly showed that elevated PCSK9 levels were related to multiple CVMMs and MACEs in stable CAD with diabetes, suggesting that plasma PCSK9 measurement could help to identify diabetic patients with CAD at higher cardiovascular risk. More studies may be needed to confirm our findings.



Cardiovasc Diabetol: 05 Oct 2020; 19:167
Peng J, Liu MM, Jin JL, Cao YX, ... Xu RX, Li JJ
Cardiovasc Diabetol: 05 Oct 2020; 19:167 | PMID: 33023603
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Impact:
Abstract

Adolescent BMI and early-onset type 2 diabetes among Ethiopian immigrants and their descendants: a nationwide study.

Simchoni M, Hamiel U, Pinhas-Hamiel O, Zucker I, ... Raz I, Twig G
Background
We assessed in a nationwide cohort the association between adolescent BMI and early-onset (< 40 years) type 2 diabetes among Israelis of Ethiopian origin.
Methods
Normoglycemic adolescents (range 16-20 years old), including 93,806 native Israelis (≥ 3rd generation in Israel) and 27,684 Israelis of Ethiopian origin, were medically assessed for military service between 1996 and 2011. Weight and height were measured. Data were linked to the Israeli National Diabetes Registry. Incident type 2 diabetes by December 31, 2016 was the outcome. Cox regression models stratified by sex and BMI categories were applied.
Results
226 (0.29%) men and 79 (0.18%) women developed diabetes during 992,980 and 530,814 person-years follow-up, respectively, at a mean age of 30.4 and 27.4 years, respectively. Among native Israeli men with normal and high (overweight and obese) BMI, diabetes incidence was 9.5 and 62.0 (per 10 person-years), respectively. The respective incidences were 46.9 and 112.3 among men of Ethiopian origin. After adjustment for sociodemographic confounders, the hazard ratios for type 2 diabetes among Ethiopian men with normal and high BMI were 3.4 (2.3-5.1) and 15.8 (8.3-30.3) respectively, compared to third-generation Israelis with normal BMI. When this analysis was limited to Israeli-born Ethiopian men, the hazard ratios were 4.4 (1.7-11.4) and 29.1 (12.9-70.6), respectively. Results persisted when immigrants of other white Caucasian origin were the reference; and among women with normal, but not high, BMI.
Conclusions
Ethiopian origin is a risk factor for early-onset type 2 diabetes among young men at any BMI, and may require selective interventions.



Cardiovasc Diabetol: 05 Oct 2020; 19:168
Simchoni M, Hamiel U, Pinhas-Hamiel O, Zucker I, ... Raz I, Twig G
Cardiovasc Diabetol: 05 Oct 2020; 19:168 | PMID: 33023586
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Impact:
Abstract

Impact of combined training with different exercise intensities on inflammatory and lipid markers in type 2 diabetes: a secondary analysis from a 1-year randomized controlled trial.

Magalhães JP, Santos DA, Correia IR, Hetherington-Rauth M, ... Bicho MD, Sardinha LB
Background
Exercise is a well-accepted strategy to improve lipid and inflammatory profile in individuals with type 2 diabetes (T2DM). However, the exercise intensity having the most benefits on lipids and inflammatory markers in patients with T2DM remains unclear. We aimed to analyse the impact of a 1-year combined high-intensity interval training (HIIT) with resistance training (RT), and a moderate continuous training (MCT) with RT on inflammatory and lipid profile in individuals with T2DM.
Methods
Individuals with T2DM (n = 80, aged 59 years) performed a 1-year randomized controlled trial and were randomized into three groups (control, n = 27; HIIT with RT, n = 25; MCT with RT, n = 28). Exercise sessions were supervised with a frequency of 3 days per week. Inflammatory and lipid profiles were measured at baseline and at 1-year follow-up. Changes in inflammatory and lipid markers were assessed using generalized estimating equations.
Results
After adjusting for sex, age and baseline moderate-to-vigorous physical activity (MVPA), we observed a time-by-group interaction for Interleukin-6 (IL-6) in both the MCT with RT (β = - 0.70, p = 0.034) and HIIT with RT (β = - 0.62, p = 0.049) groups, whereas, only the HIIT with RT group improved total cholesterol (β = - 0.03, p = 0.045) and LDL-C (β = - 0.03, p = 0.034), when compared to control. No effect was observed for C-reactive protein (CRP), cortisol, tumour necrosis factor-α (TNF-α), soluble form of the haptoglobin-hemoglobin receptor CD163 (sCD163), triglycerides and HDL-C in both groups (p > 0.05).
Conclusions
Favorable adaptations on IL-6 were observed in both the HIIT and MCT combined with RT groups following a long-term 1-year exercise intervention in individuals with T2DM. However, only the HIIT with RT prevented further derangement of total cholesterol and LDL-C, when compared to the control group. Therefore, in order to encourage exercise participation and improve inflammatory profile, either exercise protocols may be prescribed, however, HIIT with RT may have further benefits on the lipid profile. Trial registration Clinicaltrials.gov ID: NCT03144505.



Cardiovasc Diabetol: 06 Oct 2020; 19:169
Magalhães JP, Santos DA, Correia IR, Hetherington-Rauth M, ... Bicho MD, Sardinha LB
Cardiovasc Diabetol: 06 Oct 2020; 19:169 | PMID: 33028418
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Impact:
Abstract

Association between omentin-1 and major cardiovascular events after lower extremity endovascular revascularization in diabetic patients: a prospective cohort study.

Biscetti F, Nardella E, Rando MM, Cecchini AL, ... Landolfi R, Flex A
Background
Cardiovascular complications represent the major cause of morbidity and mortality of type 2 diabetes mellitus (T2DM) patients. In particular, peripheral artery disease (PAD) represents a frequent T2DM vascular complication and a risk factor for the development of major adverse cardiovascular events (MACE). Among adipokines, omentin-1 serum levels are reduced in T2DM patients with PAD and are inversely related to disease severity.
Objective
To study the relationship between omentin-1 levels, at baseline, with outcomes after endovascular procedures in T2DM patients with PAD and chronic limb-threatening ischemia (CLTI).
Research design and methods
We enrolled for our prospective non-randomized study, 207 T2DM patients with PAD and CLTI, requiring revascularization. Omentin-1 serum levels were collected before revascularization and patients incidence outcomes were evaluated at 1, 3, 6 and 12 months.
Results
Omentin-1 was reduced in patients with more severe disease (27.24 ± 4.83 vs 30.82 ± 5.48 ng/mL, p < 0.001). Overall, 84 MACE and 96 major adverse limb events (MALE) occurred during the 12-month follow-up. We observed that omentin-1 levels were lower in patients with MACE (26.02 ± 4.05 vs 31.33 ± 5.29 ng/mL, p < 0.001) and MALE (26.67 ± 4.21 vs 31.34 ± 5.54 ng/mL, p < 0.001). The association between omentin-1, MACE and MALE remained significant after adjusting for major risk factors in a multivariate analysis. Receiver operating characteristics (ROC) curve using omentin-1 levels predicted incidence events (area under the curve = 0.80).
Conclusions
We demonstrated that reduced omentin-1 levels, at baseline, are related with worse vascular outcomes in T2DM patients with PAD and CLTI undergoing an endovascular procedure.



Cardiovasc Diabetol: 06 Oct 2020; 19:170
Biscetti F, Nardella E, Rando MM, Cecchini AL, ... Landolfi R, Flex A
Cardiovasc Diabetol: 06 Oct 2020; 19:170 | PMID: 33028322
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Impact:
Abstract

High glycated albumin is an independent predictor of low response to clopidogrel in ACS patients: a cross-sectional study.

Zhao X, Li Q, Tu C, Zeng Y, Ye Y
Background
Glycated albumin (GA) is a marker of short-term glycemic control and is strongly associated with the occurrence of diabetes. Previous studies have shown an association between GA and the effect of clopidogrel therapy on ischemic stroke. However, limited information is available regarding this relationship in acute coronary syndrome (ACS) patients. In this study, we evaluated the effect of GA on platelet P2Y12 inhibition by clopidogrel in patients with ACS.
Methods
Consecutive Chinese patients with ACS who received loading or maintenance doses of clopidogrel in addition to aspirin were recruited. At least 12 h after the patient had taken the clopidogrel dose, thromboelastography (TEG) and light transmittance aggregometry (LTA) were used to calculate the quantitative platelet inhibition rate to determine clopidogrel-induced antiplatelet reactivity. A prespecified cutoff of the maximum amplitude of adenosine diphosphate (ADP)-induced platelet-fibrin clot strength > 47 mm plus an ADP-induced platelet inhibition rate < 50% assessed by TEG or ADP-induced platelet aggregation > 40% assessed by LTA to indicate low responsiveness to clopidogrel were applied for evaluation. Patients were categorized into two groups based on a GA level of 15.5%, the cutoff point indicating the development of early-phase diabetes. Multivariate linear regression analysis was used to assess the interaction of GA with clopidogrel antiplatelet therapy.
Results
A total of 1021 participants were evaluated, and 28.3% of patients (289 of 1021) had low responsiveness to clopidogrel assessed by TEG. In patients with elevated GA levels, low responsiveness to clopidogrel assessed by TEG was observed in 33.7% (139 of 412) of patients, which was a significantly higher rate than that in the lower-GA-level group (24.6%, P = 0.002). According to multivariate linear regression analysis, a GA level > 15.5% was independently associated with low responsiveness to clopidogrel after adjustment for age, sex and other conventional confounding factors. This interaction was not mediated by a history of diabetes mellitus. A GA level ≤ 15.5% was associated with a high positive value [75.4%, 95% CI 73.0-77.6%] for predicting a normal responsiveness to clopidogrel.
Conclusions
GA could be a potential biomarker to predict the effects of clopidogrel antiplatelet therapy in ACS patients and might be a clinical biomarker to guide DAPT de-escalation.



Cardiovasc Diabetol: 08 Oct 2020; 19:171
Zhao X, Li Q, Tu C, Zeng Y, Ye Y
Cardiovasc Diabetol: 08 Oct 2020; 19:171 | PMID: 33036613
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Impact:
Abstract

Use of the ankle-brachial index combined with the percentage of mean arterial pressure at the ankle to improve prediction of all-cause mortality in type 2 diabetes mellitus: an observational study.

Li YH, Sheu WH, Lee IT
Background
Peripheral artery disease (PAD) in the lower extremities is a common complication of type 2 diabetes and has been shown to be associated with mortality. The ankle-brachial index (ABI) is a simple noninvasive method to screen PAD, but this method has limited sensitivity. We hypothesized that using the percentage of mean arterial pressure (%MAP) in combination with the ABI would improve the prediction of mortality.
Methods
We retrospectively collected data from patients with type 2 diabetes who had undergone ABI and  %MAP measurements at our hospital. We separated the cohort into four groups according to their ABI and  %MAP values, and we examined whether these indices were associated with mortality.
Results
A total of 5569 patients (mean age, 65 ± 11 years) were enrolled. During the follow-up period (median, 22.9 months), 266 (4.8%) of the enrolled patients died. The combination of ABI and  %MAP was significantly more effective than ABI alone for predicting mortality (C index of 0.62, 95% confidence interval [CI] of 0.57 to 0.65 vs. C index of 0.57, 95% CI of 0.53 to 0.62; P = 0.038). In multivariate analysis (with a reference group defined by ABI > 0.90 and  %MAP ≤ 45%), the highest risk of mortality was seen in patients with ABI ≤ 0.90 and  %MAP > 45% (hazard ratio = 2.045 [95% CI 1.420, 2.945], P < 0.001).
Conclusions
The use of  %MAP alongside ABI appears to significantly improve the prediction of all-cause mortality in patients with type 2 diabetes.



Cardiovasc Diabetol: 08 Oct 2020; 19:173
Li YH, Sheu WH, Lee IT
Cardiovasc Diabetol: 08 Oct 2020; 19:173 | PMID: 33036608
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Impact:
Abstract

Blood pressure and mortality in patients with type 2 diabetes and a recent coronary event in the ELIXA trial.

Wijkman MO, Claggett B, Diaz R, Gerstein HC, ... Solomon SD, Pfeffer MA
Background
The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure.
Methods
We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization.
Results
Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10 mmHg lower SBP 1.05 (95% CI 0.99-1.12) P = 0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13 (95% CI 1.04-1.22) P = 0.002) in 2325 patients with additional CVD (index ACS+ at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10 mmHg lower SBP 0.95 (0.86-1.04) P = 0.26; P for interaction 0.005).
Conclusions
The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010.



Cardiovasc Diabetol: 11 Oct 2020; 19:175
Wijkman MO, Claggett B, Diaz R, Gerstein HC, ... Solomon SD, Pfeffer MA
Cardiovasc Diabetol: 11 Oct 2020; 19:175 | PMID: 33046070
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Impact:
Abstract

Ticagrelor monotherapy in patients with concomitant diabetes mellitus and chronic kidney disease: a post hoc analysis of the GLOBAL LEADERS trial.

Gao C, Tomaniak M, Takahashi K, Kawashima H, ... Angiolillo DJ, Serruys PW
Background
Patients with both diabetes mellitus (DM) and chronic kidney disease (CKD) are a subpopulation characterized by ultrahigh ischemic and bleeding risk after percutaneous coronary intervention. There are limited data on the impact of ticagrelor monotherapy among these patients.
Methods
In this post hoc analysis of the GLOBAL-LEADERS trial, the treatment effects of the experimental (one-month dual-antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) versus the reference regimen (12-month DAPT followed by 12-month aspirin alone) were analyzed according to DM/CKD status. The primary endpoint was a composite endpoint of all-cause death or new Q-wave myocardial infarction at 2-years. The patient-oriented composite endpoint (POCE) was defined as the composite of all-cause death, any stroke, site-reported MI and any revascularization, whereas net adverse clinical events (NACE) combined POCE with BARC type 3 or 5 bleeding events.
Results
At 2 years, the DM + /CKD + patients had significantly higher incidences of the primary endpoint (9.5% versus 3.1%, adjusted HR 2.16; 95% CI [1.66-2.80], p < 0.001), BARC type 3 or 5 bleeding events, stroke, site-reported myocardial infraction, all revascularization, POCE, and NACE, compared with the DM-/CKD- patients. Among the DM + /CKD + patients, after adjustment, there were no significant differences in the primary endpoints between the experimental and reference regimen; however, the experimental regimen was associated with lower rates of POCE (20.6% versus 25.9%, HR 0.74; 95% CI [0.55-0.99], p = 0.043, p = 0.155) and NACE (22.7% versus 28.3%, HR 0.75; 95% CI [0.56-0.99], p = 0.044, p = 0.310), which was mainly driven by a lower rate of all revascularization, as compared with the reference regimen. The landmark analysis showed that while the experimental and reference regimen had similar rates of all the clinical endpoints during the first year, the experimental regimen was associated with significantly lower rates of POCE (5.8% versus 11.0%, HR 0.49; 95% CI [0.29-0.82], p = 0.007, p = 0.040) and NACE (5.8% versus 11.2%, HR 0.48; 95% CI [0.29-0.82], p = 0.007, p = 0.013) in the second year.
Conclusion
Among patients with both DM and CKD, ticagrelor monotherapy was not associated with lower rates of all-cause death or new Q-wave, or major bleeding complications; however, it was associated with lower rates of POCE and NACE. These findings should be interpreted as hypothesis-generating.
Clinical trial registration
ClinicalTrials.gov (NCT01813435).



Cardiovasc Diabetol: 15 Oct 2020; 19:179
Gao C, Tomaniak M, Takahashi K, Kawashima H, ... Angiolillo DJ, Serruys PW
Cardiovasc Diabetol: 15 Oct 2020; 19:179 | PMID: 33066794
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Impact:
Abstract

MR-proANP and incident cardiovascular disease in patients with type 2 diabetes with and without heart failure with preserved ejection fraction.

Jensen J, Schou M, Kistorp C, Faber J, ... Vilsbøll T, Jørgensen PG
Background
Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D.
Methods
We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6-17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP.
Results
A total of 126 CV events occurred (median follow-up 4.8 [4.1-5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89-202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64-4.00] and 3.32 [1.64-6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32-56] pmol/l) did not have an increased risk (HR 2.18 [0.78-6.14]).
Conclusions
Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.



Cardiovasc Diabetol: 15 Oct 2020; 19:180
Jensen J, Schou M, Kistorp C, Faber J, ... Vilsbøll T, Jørgensen PG
Cardiovasc Diabetol: 15 Oct 2020; 19:180 | PMID: 33066783
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Impact:
Abstract

Associations of cardiac stress biomarkers with incident type 2 diabetes and changes in glucose metabolism: KORA F4/FF4 study.

Sujana C, Seissler J, Jordan J, Rathmann W, ... Thorand B, Then C
Background
High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism.
Methods
We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates.
Results
During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors.
Conclusions
High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.



Cardiovasc Diabetol: 15 Oct 2020; 19:178
Sujana C, Seissler J, Jordan J, Rathmann W, ... Thorand B, Then C
Cardiovasc Diabetol: 15 Oct 2020; 19:178 | PMID: 33066780
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Impact:
Abstract

Incidence of idiopathic cardiomyopathy in patients with type 2 diabetes in Taiwan: age, sex, and urbanization status-stratified analysis.

Chen HF, Chang YH, Lo HJ, Isfandiari MA, ... Hou WH, Li CY
Background
The epidemiology of diabetes and idiopathic cardiomyopathy have limited data. We investigated the overall and the age-, sex-, and urbanization-specific incidence and relative hazard of idiopathic cardiomyopathy in association with type 2 diabetes and various anti-diabetic medications used in Taiwan.
Methods
A total of 474,268 patients with type 2 diabetes were identified from ambulatory care and inpatient claims in 2007-2009 from Taiwan\'s National Health Insurance (NHI) database. We randomly selected 474,266 age-, sex-, and diagnosis date-matched controls from the registry of NHI beneficiaries. All study subjects were linked to ambulatory care and inpatient claims (up to the end of 2016) to identify the possible diagnosis of idiopathic cardiomyopathy. The person-year approach with Poisson assumption was used to estimate the incidence, and Cox proportional hazard regression model with Fine and Gray\'s method was used to estimate the relative hazards of idiopathic cardiomyopathy in relation to type 2 diabetes.
Results
The overall incidence of idiopathic cardiomyopathy for men and women patients, respectively, was 3.83 and 2.94 per 10,000 person-years, which were higher than the corresponding men and women controls (2.00 and 1.34 per 10,000 person-years). Compared with the control group, patients with type 2 diabetes were significantly associated with an increased hazard of idiopathic cardiomyopathy (adjusted hazard ratio [aHR]: 1.60, 95% confidence interval [CI]: 1.45-1.77] in all age and sex stratifications except in those men aged > 64 years. Patients with type 2 diabetes aged < 45 years confronted the greatest increase in the hazard of idiopathic cardiomyopathy, with an aHR of 3.35 (95% CI 2.21-5.06) and 3.48 (95% CI 1.60-7.56) for men and women, respectively. The usage of some anti-diabetic medications revealed lower risks of idiopathic cardiomyopathy.
Conclusions
In Taiwan, diabetes increased the risk of idiopathic cardiomyopathy in both sexes and in all age groups, except in men aged > 64 years. Younger patients were vulnerable to have higher HRs of idiopathic cardiomyopathy. Some anti-diabetic medications may reduce the risks of cardiomyopathy.



Cardiovasc Diabetol: 13 Oct 2020; 19:177
Chen HF, Chang YH, Lo HJ, Isfandiari MA, ... Hou WH, Li CY
Cardiovasc Diabetol: 13 Oct 2020; 19:177 | PMID: 33054769
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Impact:
Abstract

Empagliflozin reduced long-term HbA1c variability and cardiovascular death: insights from the EMPA-REG OUTCOME trial.

Ceriello A, Ofstad AP, Zwiener I, Kaspers S, George J, Nicolucci A
Background
Glucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin\'s cardiovascular death reductions.
Methods
In total, 7,020 patients with type 2 diabetes and established cardiovascular disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between cardiovascular death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment.
Results
HbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for cardiovascular death in both treatment arms with no interaction with treatment: e.g. an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615.
Conclusions
HbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin\'s reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability. ClinicalTrials.gov number, NCT01131676.



Cardiovasc Diabetol: 12 Oct 2020; 19:176
Ceriello A, Ofstad AP, Zwiener I, Kaspers S, George J, Nicolucci A
Cardiovasc Diabetol: 12 Oct 2020; 19:176 | PMID: 33050931
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Impact:
Abstract

Blood pressure levels and cardiovascular risk according to age in patients with diabetes mellitus: a nationwide population-based cohort study.

Kim HL, Kim HM, Kwon CH, Shin JH, ... Park S, Sung KC
Background
Little is known about age-specific target blood pressure (BP) in hypertensive patients with diabetes mellitus (DM). The aim of this study was to determine the BP level at the lowest cardiovascular risk of hypertensive patients with DM according to age.
Methods
Using the Korean National Health Insurance Service database, we analyzed patients without cardiovascular disease diagnosed with both hypertension and DM from January 2002 to December 2011. Primary end-point was composite cardiovascular events including cardiovascular death, myocardial infarction and stroke.
Results
Of 241,148 study patients, 35,396 had cardiovascular events during a median follow-up period of 10 years. At the age of < 70 years, the risk of cardiovascular events was lower in patients with BP < 120/70 mmHg than in those with BP 130-139/80-89 mmHg. At the age of ≥ 70, however, there were no significant differences in the risk of cardiovascular events between patients with BP 130-139/80-89 mmHg and BP < 120/70 mmHg. The risk of cardiovascular events was similar between patients with BP 130-139/80-89 mmHg and BP 120-129/70-79 mmHg, and it was significantly higher in those with BP ≥ 140/90 mmHg than in those with BP 130-139/80-89 mmHg at all ages.
Conclusions
In a cohort of hypertensive patients who had DM but no history of cardiovascular disease, lower BP was associated with lower risk of cardiovascular events especially at the age of < 70. However, low BP < 130-139/80-89 mmHg was not associated with decreased cardiovascular risk, it may be better to keep the BP of 130-139/80-89 mmHg at the age of ≥ 70.



Cardiovasc Diabetol: 18 Oct 2020; 19:181
Kim HL, Kim HM, Kwon CH, Shin JH, ... Park S, Sung KC
Cardiovasc Diabetol: 18 Oct 2020; 19:181 | PMID: 33076934
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Impact:
Abstract

Prognostic impact of admission high-sensitivity C-reactive protein in acute myocardial infarction patients with and without diabetes mellitus.

Lucci C, Cosentino N, Genovese S, Campodonico J, ... Bartorelli AL, Marenzi G
Background
High-sensitivity C-reactive protein (hs-CRP) elevation frequently occurs in acute myocardial infarction (AMI) and is associated with adverse outcomes. Since diabetes mellitus (DM) is characterized by an underlying chronic inflammation, hs-CRP may have a different prognostic power in AMI patients with and without DM.
Methods
We prospectively included 2064 AMI patients; hs-CRP was measured at hospital admission. Patients were grouped according to hs-CRP quartiles and DM status. The primary endpoint was a composite of in-hospital mortality, cardiogenic shock, and acute pulmonary edema. Two-year all-cause mortality was the secondary endpoint.
Results
Twenty-six percent (n = 548) of patients had DM and they had higher hs-CRP levels than non-DM patients (5.32 vs. 3.24 mg/L; P < 0.0001). The primary endpoint incidence in the overall population (7%, 9%, 13%, 22%; P for trend < 0.0001), in DM (14%, 9%, 21%, 27%; P = 0.0001), and non-DM (5%, 8%, 10%, 19%; P < 0.0001) patients increased in parallel with hs-CRP quartiles. The adjusted risk of the primary endpoint increased in parallel with hs-CRP quartiles in DM and non-DM patients but this relationship was less evident in DM patients. In the overall population, the adjusted OR of the primary endpoint associated with an hs-CRP value ≥ 2 mg/L was 2.10 (95% CI 1.46-3.00). For the same risk, hs-CRP was 7 and 2 mg/L in patients with and without DM. A similar behavior was observed for the secondary endpoint when the HR associated with an hs-CRP value ≥ 2 mg/L found in the overall population was 2.25 (95% CI 1.57-3.22). For the same risk, hs-CRP was 8 and 1.5 mg/L in DM and non-DM patients.
Conclusions
This study shows that hs-CRP predicts in-hospital outcome and two-year mortality in AMI patients with and without DM. However, in DM patients, the same risk of developing events as in non-DM patients is associated to higher hs-CRP levels.



Cardiovasc Diabetol: 19 Oct 2020; 19:183
Lucci C, Cosentino N, Genovese S, Campodonico J, ... Bartorelli AL, Marenzi G
Cardiovasc Diabetol: 19 Oct 2020; 19:183 | PMID: 33081810
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Impact:
Abstract

Global trend of diabetes mortality attributed to vascular complications, 2000-2016.

Ling W, Huang Y, Huang YM, Fan RR, Sui Y, Zhao HL
Background
The global epidemic of diabetes mellitus continues to grow and affects developed and developing countries alike. Intensive glycemic control is thought to modify the risks for vascular complications, hence the risks for diabetes-related death. We investigated the trend of diabetic vascular complication-related deaths between 2000 and 2016 in the global diabetes landscape.
Methods
We collected 17 years of death certificates data from 108 countries in the World Health Organization mortality database between 2000 and 2016, with coding for diabetic complications. Crude and age-standardized proportions and rates were calculated. Trend analysis was done with annual average percentage change (AAPC) of rates computed by joinpoint regression.
Results
From 2000 through 2016, 7,108,145 deaths of diabetes were reported in the 108 countries. Among them, 26.8% (1,904,787 cases) were attributed to vascular complications in damaged organs, including the kidneys (1,355,085 cases, 71.1%), peripheral circulatory (515,293 cases, 27.1%), nerves (28,697 cases, 1.5%) and eyes (5751 cases, 0.3%). Overall, the age-standardized proportion of vascular complication-related mortality was 267.8 [95% confidence interval (95% CI), 267.5-268.1] cases per 1000 deaths and the rate was 53.6 (95% CI 53.5-53.7) cases per 100,000 person-years. Throughout the 17-year period, the overall age-standardized proportions of deaths attributable to vascular complications had increased 37.9%, while the overall age-standardized mortality rates related to vascular complications had increased 30.8% (AAPC = 1.9% [1.4-2.4%, p < 0.05]). These increases were predominantly driven by a 159.8% increase in the rate (AAPC = 2.7% [1.2-4.3%, p < 0.05]) from renal complications. Trends in the rates and AAPC of deaths varied by type of diabetes and of complications, as well as by countries, regions and domestic income.
Conclusion
Diabetic vascular complication-related deaths had increased substantially during 2000-2016, mainly driven by the increased mortality of renal complications.



Cardiovasc Diabetol: 19 Oct 2020; 19:182
Ling W, Huang Y, Huang YM, Fan RR, Sui Y, Zhao HL
Cardiovasc Diabetol: 19 Oct 2020; 19:182 | PMID: 33081808
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Impact:
Abstract

Distinct non-ischemic myocardial late gadolinium enhancement lesions in patients with type 2 diabetes.

Bojer AS, Sørensen MH, Vejlstrup N, Goetze JP, Gæde P, Madsen PL
Background
Cardiovascular magnetic resonance imaging (CMR) have described localised non-ischemic late gadolinium enhancement (LGE) lesions of prognostic importance in various non-ischemic cardiomyopathies. Ischemic LGE lesions are prevalent in diabetes (DM), but non-ischemic LGE lesions have not previously been described or systematically studied in DM.
Methods
296 patients with type 2 DM (T2DM) and 25 sex-matched control subjects underwent echocardiography and CMR including adenosine-stress perfusion, T-mapping and LGE.
Results
264 patients and all control subjects completed the CMR protocol. 78.4% of patients with T2DM had no LGE lesions; 11.0% had ischemic LGE lesions only; 9.5% had non-ischemic LGE lesions only; and 1.1% had both one ischemic and one non-ischemic lesion. The non-ischemic LGE lesions were situated mid-myocardial in the basal lateral or the basal inferolateral part of the left ventricle and the affected segments showed normal to high wall thickness and normal contraction. Patients with non-ischemic LGE lesions in comparison with patients without LGE lesions had increased myocardial mass (150 ± 34 vs. 133 ± 33 g, P = 0.02), average E/e\'(9.9 IQR8.7-12.6 vs. 8.8 IQR7.4-10.7, P = 0.04), left atrial maximal volume (102 IQR84.6-115.2 vs. 91 IQR75.2-100.0 mL, P = 0.049), NT-proBNP (8.9 IQR5.9-19.7 vs. 5.9 IQR5.9-10.1 µmol/L, P = 0.02) and high-sensitive troponin (15.6 IQR13.0-26.1 vs. 13.0 IQR13.0-14.6 ng/L, P = 0.007) and a higher prevalence of retinopathy (48 vs. 25%, P = 0.009) and autonomic neuropathy (52 vs. 30.5%, P = 0.005).
Conclusion
A specific LGE pattern with lesions in the basal lateral or the basal inferolateral part of the left ventricle was found in patients with type 2 diabetes. Trial registration https://www.clinicaltrials.gov . Unique identifier: NCT02684331.



Cardiovasc Diabetol: 21 Oct 2020; 19:184
Bojer AS, Sørensen MH, Vejlstrup N, Goetze JP, Gæde P, Madsen PL
Cardiovasc Diabetol: 21 Oct 2020; 19:184 | PMID: 33092588
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Impact:
Abstract

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes.

Schernthaner G, Shehadeh N, Ametov AS, Bazarova AV, ... Tankova T, Visockienė Ž

The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.



Cardiovasc Diabetol: 22 Oct 2020; 19:185
Schernthaner G, Shehadeh N, Ametov AS, Bazarova AV, ... Tankova T, Visockienė Ž
Cardiovasc Diabetol: 22 Oct 2020; 19:185 | PMID: 33097060
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Impact:
Abstract

Serum alkaline phosphatase levels and the risk of new-onset diabetes in hypertensive adults.

Zhang Y, Zhou C, Li J, Zhang Y, ... Xu X, Qin X
Background
The association between alkaline phosphatase (ALP) and incident diabetes remains uncertain. Our study aimed to investigate the prospective relation of serum ALP with the risk of new-onset diabetes, and explore possible effect modifiers, in hypertensive adults.
Methods
A total 14,393 hypertensive patients with available ALP measurements and without diabetes and liver disease at baseline were included from the China Stroke Primary Prevention Trial (CSPPT). The primary outcome was new-onset diabetes, defined as physician-diagnosed diabetes or use of glucose-lowering drugs during follow-up, or fasting glucose ≥ 7.0 mmol/L at the exit visit. The secondary study outcome was new-onset impaired fasting glucose (IFG), defined as FG < 6.1 mmol/L at baseline and ≥ 6.1 but < 7.0 mmol/L at the exit visit.
Results
Over a median of 4.5 years follow-up, 1549 (10.8%) participants developed diabetes. Overall, there was a positive relation of serum ALP and the risk of new-onset diabetes (per SD increment, adjusted OR, 1.07; 95% CI: 1.01, 1.14) and new-onset IFG (per SD increment, adjusted OR, 1.07; 95% CI: 1.02, 1.14). Moreover, a stronger positive association between baseline ALP (per SD increment) with new-onset diabetes was found in participants with total homocysteine (tHcy) < 10 μmol/L (adjusted OR, 1.24; 95% CI: 1.10, 1.40 vs. ≥ 10 μmol/L: adjusted OR, 1.03; 95% CI: 0.96, 1.10; P-interaction = 0.007) or FG ≥ 5.9 mmol/L (adjusted OR, 1.16; 95% CI: 1.07, 1.27 vs. < 5.9 mmol/L: adjusted OR, 1.00; 95% CI: 0.93, 1.08; P-interaction = 0.009) Conclusions: In this non-diabetic, hypertensive population, higher serum ALP was significantly associated with the increased risk of new-onset diabetes, especially in those with lower tHcy or higher FG levels. Clinical trial registration-URL Trial registration: NCT00794885 (clinicaltrials.gov). Retrospectively registered November 20, 2008.



Cardiovasc Diabetol: 23 Oct 2020; 19:186
Zhang Y, Zhou C, Li J, Zhang Y, ... Xu X, Qin X
Cardiovasc Diabetol: 23 Oct 2020; 19:186 | PMID: 33099298
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Abstract

Sodium-glucose cotransporter 2 inhibitor versus metformin as first-line therapy in patients with type 2 diabetes mellitus: a multi-institution database study.

Chen TH, Li YR, Chen SW, Lin YS, ... Chu PH, Wu VC
Background
Sodium-glucose co-transporter 2 inhibitors (SGLT2i) has shown evidence of cardiovascular benefit in patients with type 2 diabetes mellitus (T2DM). Currently metformin is the guideline-recommended first-line treatment. We aimed to investigate the benefit of SGLT2i vs metformin as first-line therapy.
Methods
Electronic medical records from Chang Gung Research Database during 2016-2019 were retrieved for patients with T2DM. Patients aged < 20, not receiving anti-diabetic medication, first-line treatment neither metformin nor SGLT2i were excluded. Primary outcomes were heart failure hospitalization, acute coronary syndrome, ischemic stroke, and all-cause mortality. Patients were followed up for events or December 31, 2019, whichever comes first.
Results
After exclusion criteria, a total of 41,020 patients with T2DM were eligible for analysis. There were 1100 patients with SGLT2i as first-line and 39,920 patients with metformin as first-line treatment. IPTW was used for propensity score matching. During one year follow-up, the hazard ratio (HR) of patients on SGLT2i as first-line treatment to patients on metformin as first-line treatment were HR 0.47 (95% CI 0.41-0.54, p < 0.0001) in heart failure hospitalization, HR 0.50 (95% CI 0.41-0.61, p < 0.0001) in acute coronary syndrome, HR 1.21 (95% CI 1.10-1.32, p < 0.0001) in ischemic stroke, and HR 0.49 (95% CI 0.44-0.55, p < 0.0001) in all-cause mortality.
Conclusions
In patients with T2DM, SGLT2i as first-line treatment may be associated with decreased events of heart failure hospitalization, acute coronary syndrome, and all-cause mortality, compared with metformin as first-line treatment. However, there may be an increased events of ischemic stroke using SGLT2i compared to metformin.



Cardiovasc Diabetol: 08 Nov 2020; 19:189
Chen TH, Li YR, Chen SW, Lin YS, ... Chu PH, Wu VC
Cardiovasc Diabetol: 08 Nov 2020; 19:189 | PMID: 33167990
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Impact:
Abstract

Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance.

Macchi C, Favero C, Ceresa A, Vigna L, ... Bollati V, Ruscica M
Background
Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk.
Results
In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9.
Conclusions
This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.



Cardiovasc Diabetol: 02 Nov 2020; 19:187
Macchi C, Favero C, Ceresa A, Vigna L, ... Bollati V, Ruscica M
Cardiovasc Diabetol: 02 Nov 2020; 19:187 | PMID: 33143700
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Impact:
Abstract

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors.

Ling AW, Chan CC, Chen SW, Kao YW, ... Chan YH, Chu PH
Background
Sodium glucose cotransporter 2 inhibitor (SGLT2i) reduces the risk of hard cardiovascular endpoints in type 2 diabetes mellitus (T2DM) patients with/without established cardiovascular diseases. Whether SGLT2i is associated with a lower risk of new-onset atrial fibrillation (AF) in T2DM patients is unclear. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i compared to dipeptidyl peptidase-4 inhibitor (DPP4i) among a longitudinal cohort of diabetic patients.
Methods
We used medical data from a multi-center healthcare provider in Taiwan, which included a total of 15,606 and 12,383 patients treated with SGLT2i and DPP4i, respectively, from June 1, 2016 to December 31, 2018. We used propensity-score weighting to balance covariates across study groups. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the index drug, or the end of the study period, whichever occurred first.
Results
Overall, 55%, 45%, and 0% of the patients were treated with empagliflozin, dapagliflozin, and canagliflozin, respectively. Most patients in the DPP4i group were prescribed with linagliptin (51%), followed by sitagliptin (24%), saxagliptin (13%), vildagliptin (8%) and alogliptin (5%). The use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i after propensity-score weighting [hazard ratio: 0.61; 95% confidential interval: 0.50-0.73; P < 0.001]. Subgroup analysis revealed that the use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i across several subgroups including old age, female in gender, the presence of cardiovascular disease, hemoglobin A1c [Formula: see text] 8%, and chronic kidney disease. The advantage of SGLT2i over DPP4i persisted with different SGLT2i (dapagliflozin or empagliflozin) and either low- or standard-dose SGLT2i.
Conclusions
SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i among T2DM patients in real-world practice.



Cardiovasc Diabetol: 05 Nov 2020; 19:188
Ling AW, Chan CC, Chen SW, Kao YW, ... Chan YH, Chu PH
Cardiovasc Diabetol: 05 Nov 2020; 19:188 | PMID: 33158436
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Impact:
Abstract

Body mass index and cardiovascular outcomes in patients with acute coronary syndrome by diabetes status: the obesity paradox in a Korean national cohort study.

Park SJ, Ha KH, Kim DJ
Background
The \"obesity paradox\" has not been elucidated in the long-term outcomes of acute coronary syndrome (ACS). We investigated the association between obesity and cardiovascular (CV) outcomes in ACS patients with and without diabetes.
Methods
We identified 6978 patients with ACS aged 40-79 years from the Korean National Health Insurance Service-Health Screening Cohort between 2002 and 2015. Baseline body mass index (BMI) was categorized as underweight (< 18.5 kg/m), normal weight (18.5-22.9 kg/m), overweight (23.0-24.9 kg/m), obese class I (25.0-29.9 kg/m), and obese class II (≥ 30.0 kg/m). The primary outcome was major adverse CV events (MACE)-CV death, myocardial infarction (MI), and stroke. The secondary outcomes were the individual components of MACE, hospitalization for heart failure (HHF), and all-cause death.
Results
After adjustment for confounding variables, compared to normal-weight patients without diabetes (reference group), obese class I patients with and without diabetes had a lower risk of MACE, but only significant in patients without diabetes (with diabetes: hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.78-1.14; without diabetes: HR 0.78, 95% CI 0.62-0.97). Obese class II patient with diabetes had a higher risk of MACE with no statistical significance (HR 1.14, 95% CI 0.82-1.59). Underweight patients with and without diabetes had a higher risk of MACE, but only significant in patients with diabetes (with diabetes: HR 1.79, 95% CI 1.24-2.58; without diabetes: HR 1.23, 95% CI 0.77-1.97).
Conclusion
In ACS patients, obesity had a protective effect on CV outcomes, especially in patients without diabetes.



Cardiovasc Diabetol: 09 Nov 2020; 19:191
Park SJ, Ha KH, Kim DJ
Cardiovasc Diabetol: 09 Nov 2020; 19:191 | PMID: 33172464
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Impact:
Abstract

Cholesterol lowering therapies and achievement of targets for primary and secondary cardiovascular prevention in type 2 diabetes: unmet needs in a large population of outpatients at specialist clinics.

Morieri ML, Avogaro A, Fadini GP
Background
The well-established benefit of Low-Dense-Lipoprotein-cholesterol (LDL-c) lowering treatments (LLTs) has led clinical guidelines to lower the cardiovascular prevention targets. Despite this, there is a surprising scarcity of real-world studies (RWS) evaluating whether recommendations are applied in the routine clinical management of patients with type 2 diabetes (T2D). We therefore evaluated, in a large RWS, the pattern of LLTs use and the achievement of LDL-c targets in patients with T2D in Italian diabetes specialist clinics.
Methods
We collected data from 46 diabetes outpatient clinics (following 281,381 subjects), including 104,726 T2D patients, for whom use of LLTs between 2015 and 2016 was ascertained. We used the 2016 and 2019 European Atherosclerosis Society and European Society of Cardiology (EAS-ESC) guidelines to define cardiovascular risk categories, LDL-c targets, and the expected LDL-c reduction and cardiovascular benefit achievable with LLT intensification.
Results
63,861 patients (61.0%) were on statin therapy, 9.2% of whom were also on ezetimibe. Almost all subjects were at high (29.3%) or very high (70.4%) cardiovascular risk, including 17% being in secondary prevention. Among very high-risk patients, 35% were not on statin despite half of them had LDL-c > 2.6 mmol/l, and only 15% of those on statins had LDL-c < 1.4 mmol/l. 83% of subjects in secondary prevention were on a statin, but half of them had LDL-c > 1.8 mmol/l. Overall, 35% and 14% of subjects achieved the LDL-c targets as suggested by 2016 and 2019 EAS-ESC Guidelines, respectively. Based on anticipated response to treatment, we estimated that 38% of the entire population would require high-intensity-statin (HI-statin), 27% a combination of HI-statin plus ezetimibe, and 27% the addition of proprotein-convertase-subtilisin/kexin-9 (PCSK9) inhibitors. These LLT intensifications would reduce the incidence of cardiovascular events by 32%, from 23.511 to 16.022 events per 100.000 patients/10-years (incidence-rate-ratio 0.68; 95% C.I 0.67-0.70, p < 0.001).
Conclusions
Despite the increase in use of LLT in T2D over the last decades, a large proportion of subjects with T2D did not achieve their LDL-c targets. Given the very high cardiovascular risk of these patients, improving LLT is expected to have a dramatic impact on cardiovascular event prevention.



Cardiovasc Diabetol: 09 Nov 2020; 19:190
Morieri ML, Avogaro A, Fadini GP
Cardiovasc Diabetol: 09 Nov 2020; 19:190 | PMID: 33172454
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Impact:
Abstract

Prognostic irrelevance of plaque vulnerability following plaque sealing in high-risk patients with type 2 diabetes: an optical coherence tomography study.

Dettori R, Milzi A, Burgmaier K, Almalla M, ... Reith S, Burgmaier M
Background
Type 2 diabetes mellitus (T2DM) is associated with an increased cardiovascular risk related at least in part to a more vulnerable plaque phenotype. However, patients with T2DM exhibit also an increased risk following percutaneous coronary intervention (PCI). It is unknown if plaque vulnerability of a treated lesion influences cardiovascular outcomes in patients with T2DM. In this study, we aimed to assess the association of plaque morphology as determined by optical coherence tomography (OCT) with cardiovascular outcome following PCI in high-risk patients with T2DM.
Methods
81 patients with T2DM and OCT-guided PCI were recruited. Pre-interventional OCT and systematic follow-up of median 66.0 (IQR = 8.0) months were performed.
Results
During follow-up, 24 patients (29.6%) died. The clinical parameters age (HR 1.16 per year, 95% CI 1.07-1.26, p < 0.001), diabetic polyneuropathy (HR 3.58, 95% CI 1.44-8.93, p = 0.006) and insulin therapy (HR 3.25, 95% CI 1.21-8.70, p = 0.019) predicted mortality in T2DM patients independently. Among OCT parameters only calcium-volume-index (HR 1.71 per 1000°*mm, 95% CI 1.21-2.41, p = 0.002) and lesion length (HR 1.93 per 10 mm, 95% CI 1.02-3.67, p = 0.044) as parameters describing atherosclerosis extent were significant independent predictors of mortality. However, classical features of plaque vulnerability, such as thickness of the fibrous cap, the extent of the necrotic lipid core and the presence of macrophages had no significant predictive value (all p = ns).
Conclusion
Clinical parameters including those describing diabetes severity as well as OCT-parameters characterizing atherosclerotic extent but not classical features of plaque vulnerability predict mortality in T2DM patients following PCI. These data suggest that PCI may provide effective plaque sealing resulting in limited importance of local target lesion vulnerability for future cardiovascular events in high-risk patients with T2DM.



Cardiovasc Diabetol: 11 Nov 2020; 19:192
Dettori R, Milzi A, Burgmaier K, Almalla M, ... Reith S, Burgmaier M
Cardiovasc Diabetol: 11 Nov 2020; 19:192 | PMID: 33183273
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Impact:
Abstract

Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk.

Giorgino F, Vora J, Fenici P, Solini A

Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.



Cardiovasc Diabetol: 21 Nov 2020; 19:196
Giorgino F, Vora J, Fenici P, Solini A
Cardiovasc Diabetol: 21 Nov 2020; 19:196 | PMID: 33222693
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Impact:
Abstract

Risk for cardiovascular disease associated with metabolic syndrome and its components: a 13-year prospective study in the RIVANA cohort.

Guembe MJ, Fernandez-Lazaro CI, Sayon-Orea C, Toledo E, Moreno-Iribas C
Background
We aimed to investigate the association of metabolic syndrome (MetS) and its single components with cardiovascular risk and estimated their impact on the prematurity of occurrence of cardiovascular events using rate advancement periods (RAPs).
Methods
We performed prospective analyses among 3976 participants (age range: 35-84, 55% female) in the Vascular Risk in Navarre (RIVANA) Study, a Mediterranean population-based cohort. MetS was defined based on the modified criteria of the American Heart Association/National Heart, Lung, and Blood Institute and the International Diabetes Federation. The primary endpoint was major cardiovascular event (a composite of myocardial infarction, stroke, or mortality from cardiovascular causes). Secondary endpoints were incidence of non-fatal myocardial infarction and non-fatal stroke, cardiovascular mortality, and all-cause mortality. Cox proportional hazards models, adjusted for potential confounders, were fitted to evaluate the association between MetS and its single components at baseline with primary and secondary endpoints.
Results
During a median follow-up of 12.8 years (interquartile range, 12.5-13.1), we identified 228 primary endpoint events. MetS was associated with higher risk of incidence of major cardiovascular event, cardiovascular and all-cause mortality, but was neither associated with higher risk of myocardial infarction nor stroke. Compared with participants without MetS, the multivariable hazard ratio (95% confidence interval [CI]) among participants with MetS was 1.32 (1.01-1.74) with RAP (95% CI) of 3.23 years (0.03, 6.42) for major cardiovascular event, 1.64 (1.03-2.60) with RAP of 3.73 years (0.02, 7.45) for cardiovascular mortality, and 1.45 (1.17-1.80) with RAP of 3.24 years (1.21, 5.27) for all-cause mortality. The magnitude of the associations of the single components of MetS was similar than the predicted by MetS. Additionally, for each additional trait of MetS, incidence of major cardiovascular event relatively increased by 22% (1.22, 95% CI 1.09-1.36) with RAP of 2.31 years (0.88, 3.74).
Conclusions
MetS was independently associated with CVD risk, cardiovascular and all-cause mortality. Components of the MetS were associated with similar magnitude of increased CVD, which suggests that MetS was not in excess of the level explained by the presence of its single components. Further research should explore the association of different combinations of the components of MetS with CVD.



Cardiovasc Diabetol: 21 Nov 2020; 19:195
Guembe MJ, Fernandez-Lazaro CI, Sayon-Orea C, Toledo E, Moreno-Iribas C
Cardiovasc Diabetol: 21 Nov 2020; 19:195 | PMID: 33222691
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Abstract

Association of serum Cyr61 levels with peripheral arterial disease in subjects with type 2 diabetes.

Feng B, Xu G, Sun K, Duan K, Shi B, Zhang N
Background
The prevalence of peripheral artery disease (PAD) is obviously increased in patients with diabetes. Existing evidence shows that cysteine-rich angiogenic inducer 61 (Cyr61), a 40-kD secreted protein, plays important roles in regulating cellular physiological processes. Recent studies have demonstrated a significant correlation between serum Cyr61 and atherosclerosis. However, the relationship between Cyr61 levels and PAD in patients with type 2 diabetes (T2DM) remains obscure.
Methods
Data from a total of 306 subjects with T2DM were cross-sectionally analysed. The extent of PAD was determined by using the Fontaine classification, which defines four stages. We measured serum Cyr61 concentrations by ELISA in subjects with and without PAD at Fontaine\'s stage II, III, or IV. Logistic regression models were used to examine the independent association of Cyr61 with PAD.
Results
Out of the 306 subjects enrolled, 150 were free from PAD, while 156 had clinically significant PAD. In subjects with PAD, the prevalences of Fontaine classification stages II, III and IV were 48.7%, 32.1%, and 19.2%, respectively. Patients with more advanced PAD had significantly higher Cyr61 (P for trend < 0.001). The prevalence of PAD on the basis of severity increased with increasing Cyr61 quartiles (all P values for trends < 0.001), and the severity of PAD was positively correlated with Cyr61 quartiles (r = 0.227, P = 0.006). The association of Cyr61 levels with PAD remained after adjusting for major risk factors in a logistic regression analysis.
Conclusions
Our results demonstrated that Cyr61 was significantly increased in PAD patients with T2DM and that Cyr61 levels were positively associated with disease severity. Cyr61 could be a promising biomarker and further studies are needed to assess its clinical utility.



Cardiovasc Diabetol: 21 Nov 2020; 19:194
Feng B, Xu G, Sun K, Duan K, Shi B, Zhang N
Cardiovasc Diabetol: 21 Nov 2020; 19:194 | PMID: 33222686
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Impact:
Abstract

Association between adipocyte fatty acid-binding protein with left ventricular remodelling and diastolic function in type 2 diabetes: a prospective echocardiography study.

Wu MZ, Lee CH, Chen Y, Yu SY, ... Lam SK, Yiu KH
Background
The relationship between adipocyte fatty acid-binding protein (AFABP) and cardiac remodelling has been reported in cross-sectional studies, although with conflicting results. Type 2 diabetes mellitus (T2DM) is associated with left ventricular (LV) hypertrophy and diastolic dysfunction, as well as elevated circulating AFABP levels. Here we investigated prospectively the association between AFABP with the longitudinal changes of cardiac remodelling and diastolic dysfunction in T2DM.
Methods
Circulating AFABP levels were measured in 176 T2DM patients without cardiovascular diseases (CVD) at baseline. All participants received detailed transthoracic echocardiography both at baseline and after 1 year. Multivariable linear and Cox regression analyses were used to evaluate the associations of circulating AFABP levels with changes in echocardiography parameters and incident major adverse cardiovascular events (MACE), respectively.
Results
The median duration between baseline and follow-up echocardiography assessments was 28 months. Higher sex-specific AFABP quartiles at baseline were associated with increase in LV mass and worsening of average E/e\' (all P < 0.01). Multivariable linear regression demonstrated that AFABP in the highest quartile was independently associated with both increase in LV mass (β = 0.89, P < 0.01) and worsening of average E/e\' (β = 0.57, P < 0.05). Moreover, multivariable Cox regression analysis showed that elevated baseline circulating AFABP level independently predicted incident MACE (HR 2.65, 95% CI 1.16-6.05, P < 0.05) after adjustments for age, sex, body mass index, glycated haemoglobin, hypertension, dyslipidemia and presence of chronic kidney disease.
Conclusion
Circulating AFABP level at baseline predicted the development of LV hypertrophy, diastolic dysfunction and MACE in T2DM patients without CVD.



Cardiovasc Diabetol: 23 Nov 2020; 19:197
Wu MZ, Lee CH, Chen Y, Yu SY, ... Lam SK, Yiu KH
Cardiovasc Diabetol: 23 Nov 2020; 19:197 | PMID: 33234149
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Impact:
Abstract

Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient.

Nantsupawat T, Wongcharoen W, Chattipakorn SC, Chattipakorn N

Metformin has been shown to have various cardiovascular benefits beyond its antihyperglycemic effects, including a reduction in stroke, heart failure, myocardial infarction, cardiovascular death, and all-cause mortality. However, the roles of metformin in cardiac arrhythmias are still unclear. It has been shown that metformin was associated with decreased incidence of atrial fibrillation in diabetic patients with and without myocardial infarction. This could be due to the effects of metformin on preventing the structural and electrical remodeling of left atrium via attenuating intracellular reactive oxygen species, activating 5\' adenosine monophosphate-activated protein kinase, improving calcium homeostasis, attenuating inflammation, increasing connexin-43 gap junction expression, and restoring small conductance calcium-activated potassium channels current. For ventricular arrhythmias, in vivo reports demonstrated that activation of 5\' adenosine monophosphate-activated protein kinase and phosphorylated connexin-43 by metformin played a key role in ischemic ventricular arrhythmias reduction. However, metformin failed to show anti-ventricular arrhythmia benefits in clinical trials. In this review, in vitro and in vivo reports regarding the effects of metformin on both atrial arrhythmias and ventricular arrhythmias are comprehensively summarized and presented. Consistent and controversial findings from clinical trials are also summarized and discussed. Due to limited numbers of reports, further studies are needed to elucidate the mechanisms and effects of metformin on cardiac arrhythmias. Furthermore, randomized controlled trials are needed to clarify effects of metformin on cardiac arrhythmias in human.



Cardiovasc Diabetol: 23 Nov 2020; 19:198
Nantsupawat T, Wongcharoen W, Chattipakorn SC, Chattipakorn N
Cardiovasc Diabetol: 23 Nov 2020; 19:198 | PMID: 33234131
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Impact:
Abstract

Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis.

Dagenais GR, Rydén L, Leiter LA, Lakshmanan M, ... Riddle MC, Gerstein HC
Background
The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants Methods: We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models.
Results
Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82-0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80-0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87-0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82-0.99) p = 0.028].
Conclusions
These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.
Clinical trial registration
https://www.clinicaltrials.gouv . Unique Identifier NCT01394952).



Cardiovasc Diabetol: 24 Nov 2020; 19:199
Dagenais GR, Rydén L, Leiter LA, Lakshmanan M, ... Riddle MC, Gerstein HC
Cardiovasc Diabetol: 24 Nov 2020; 19:199 | PMID: 33239067
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Abstract

Metabolic syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a post hoc analyses of the EMPA-REG OUTCOME trial.

Ferreira JP, Verma S, Fitchett D, Ofstad AP, ... Zinman B, Inzucchi SE
Background
Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial.
Methods
A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10 mg or 25 mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models.
Results
MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR = 1.73 (95% CI 1.01-2.98), heart failure hospitalization: HR = 2.64 (95% CI 1.22, 5.72), and new or worsening nephropathy: HR = 3.11 (95% CI 2.17-4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS.
Conclusions
A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS. Trial registration Clinical Trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.



Cardiovasc Diabetol: 25 Nov 2020; 19:200
Ferreira JP, Verma S, Fitchett D, Ofstad AP, ... Zinman B, Inzucchi SE
Cardiovasc Diabetol: 25 Nov 2020; 19:200 | PMID: 33243221
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Abstract

Marked effects of novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate in severe hypertriglyceridemia: preliminary report.

Iitake C, Masuda D, Koseki M, Yamashita S
Background
Currently available treatments have only been partly successful in patients with severe hypertriglyceridemia, including those with high serum triglycerides above 1,000 mg/dL (11.3 mmol/L), who often suffer from acute pancreatitis. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) which has been developed as an affordable oral tablet in Japan. We herein report the first three patients with severe hypertriglyceridemia who were successfully treated with pemafibrate.
Methods
Three patients with fasting serum triglyceride (TG) levels above 1,000 mg/dL (11.3 mmol/L) were treated with pemafibrate (0.2-0.4 mg/day, 0.1-0.2 mg BID).
Results
Serum TGs decreased from 2,000-3,000 mg/dL (22.6-33.9 mmol/L) to < 250 mg/dL (2.8 mmol/L) without adverse effects in all three patients. Serum TGs in Patient 1 and 2 decreased from 1,326 mg/dL (15.0 mmol/L) to 164 mg/dL (1.9 mmol/L) and from 2,040 mg/dL (23.1 mmol/L) to 234 mg/dL (2.6 mmol/L), respectively. Patient 3 with type 2 diabetes and 12.1% (109 mmol/mol) hemoglobin A1c had a TG level of 2,300 mg/dL (26.0 mmol/L). Even after glycemic control improved, TG remained high. After pemafibrate administration, TG decreased to 200 mg/dL (2.3 mmol/L). All patients showed no serious adverse events.
Conclusions
Pemafibrate demonstrated potential efficacy and safety for severe hypertriglyceridemia which may contribute to the prevention of acute pancreatitis, in a manner that can be easily prescribed and used as an oral tablet.



Cardiovasc Diabetol: 26 Nov 2020; 19:201
Iitake C, Masuda D, Koseki M, Yamashita S
Cardiovasc Diabetol: 26 Nov 2020; 19:201 | PMID: 33246467
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Abstract

Cardiac resynchronization therapy and its effects in patients with type 2 DIAbetes mellitus OPTimized in automatic vs. echo guided approach. Data from the DIA-OPTA investigators.

Sardu C, Paolisso P, Ducceschi V, Santamaria M, ... Ruocco A, Marfella R
Objectives
To evaluate the effects of cardiac resynchronization therapy (CRTd) in patients with type 2 diabetes mellitus (T2DM) optimized via automatic vs. echocardiography-guided approach.
Background
The suboptimal atrio-ventricular (AV) and inter-ventricular (VV) delays optimization reduces CRTd response. Therefore, we hypothesized that automatic CRTd optimization might improve clinical outcomes in T2DM patients.
Methods
We designed a prospective, multicenter study to recruit, from October 2016 to June 2019, 191 consecutive failing heart patients with T2DM, and candidate to receive a CRTd. Study outcomes were CRTd responders rate, hospitalizations for heart failure (HF) worsening, cardiac deaths and all cause of deaths in T2DM patients treated with CRTd and randomly optimized via automatic (n 93) vs. echocardiography-guided (n 98) approach at 12 months of follow-up.
Results
We had a significant difference in the rate of CRTd responders (68 (73.1%) vs. 58 (59.2%), p 0.038), and hospitalizations for HF worsening (12 (16.1%) vs. 22 (22.4%), p 0.030) in automatic vs. echocardiography-guided group of patients. At multivariate Cox regression analysis, the automatic guided approach (3.636 [1.271-10.399], CI 95%, p 0.016) and baseline highest values of atrium pressure (automatic SonR values, 2.863 [1.537-6.231], CI 95%, p 0.006) predicted rate of CRTd responders. In automatic group, we had significant difference in SonR values comparing the rate of CRTd responders vs. non responders (1.24 ± 0.72 g vs. 0.58 ± 0.46 g (follow-up), p 0.001), the rate of hospitalizations for HF worsening events (0.48 ± 0.29 g vs. 1.18 ± 0.43 g, p 0.001), and the rate of cardiac deaths ( 1.13 ± 0.72 g vs. 0.65 ± 0.69 g, p 0.047).
Conclusions
Automatic optimization increased CRTd responders rate, and reduced hospitalizations for HF worsening. Intriguingly, automatic CRTd and highest baseline values of SonR could be predictive of CRTd responders. Notably, there was a significant difference in SonR values for CRTd responders vs. non responders, and about hospitalizations for HF worsening and cardiac deaths. Clinical trial ClinicalTrials.gov Identifier NCT04547244.



Cardiovasc Diabetol: 27 Nov 2020; 19:202
Sardu C, Paolisso P, Ducceschi V, Santamaria M, ... Ruocco A, Marfella R
Cardiovasc Diabetol: 27 Nov 2020; 19:202 | PMID: 33248462
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Abstract

Impact of diabetes mellitus on the early-phase arterial healing after drug-eluting stent implantation.

Ishihara T, Sotomi Y, Tsujimura T, Iida O, ... Higuchi Y, Mano T
Background
Early arterial healing after drug-eluting stent (DES) implantation may enable short dual-antiplatelet therapy (DAPT) strategy. The impact of diabetes mellitus (DM) on this healing has not been elucidated. We used coronary angioscopy (CAS) to compare intravascular status of DM and non-DM patients in the early phase after DES implantation.
Methods
This study was a multicenter retrospective observational study. We analyzed CAS findings of 337 lesions from 270 patients evaluated 3-5 months after DES implantation. We divided the lesion into two groups: DM (n = 149) and non-DM (n = 188). We assessed neointimal coverage (NIC) grades (dominant, maximum and minimum), thrombus adhesion and maximum yellow color grade. NIC was graded as follows: grade 0, stent struts were not covered; grade 1, stent struts were covered by thin layer; grade 2, stent struts were buried under neointima. Yellow color was graded as grade 0, white; grade 1, light yellow; grade 2, yellow; grade 3, intensive yellow.
Results
Minimum NIC grade was significantly lower in DM than in non-DM groups (p = 0.002), whereas dominant and maximum NIC grades were similar between them (p = 0.59 and p = 0.94, respectively), as were thrombus adhesion (44.3% vs. 38.8%, p = 0.32) and maximum yellow color grade (p = 0.78). A multivariate analysis demonstrated that DM was an independent predictor of minimum NIC of grade 0 (odds ratio: 2.14, 95% confidence interval: 1.19-3.86, p = 0.011).
Conclusions
DM patients showed more uncovered struts than non-DM patients 3-5 months after DES implantation, suggesting that the recent ultra-short DAPT strategy might not be easily applied to DM patients.



Cardiovasc Diabetol: 01 Dec 2020; 19:203
Ishihara T, Sotomi Y, Tsujimura T, Iida O, ... Higuchi Y, Mano T
Cardiovasc Diabetol: 01 Dec 2020; 19:203 | PMID: 33267863
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This program is still in alpha version.