Journal: Cardiovasc Diabetol

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Abstract

Risk for recurrent cardiovascular disease events among patients with diabetes and chronic kidney disease.

Hubbard D, Colantonio LD, Rosenson RS, Brown TM, ... Farkouh ME, Muntner P
Background
Adults who have experienced multiple cardiovascular disease (CVD) events have a very high risk for additional events. Diabetes and chronic kidney disease (CKD) are each associated with an increased risk for recurrent CVD events following a myocardial infarction (MI).
Methods
We compared the risk for recurrent CVD events among US adults with health insurance who were hospitalized for an MI between 2014 and 2017 and had (1) CVD prior to their MI but were free from diabetes or CKD (prior CVD), and those without CVD prior to their MI who had (2) diabetes only, (3) CKD only and (4) both diabetes and CKD. We followed patients from hospital discharge through December 31, 2018 for recurrent CVD events including coronary, stroke, and peripheral artery events.
Results
Among 162,730 patients, 55.2% had prior CVD, and 28.3%, 8.3%, and 8.2% had diabetes only, CKD only, and both diabetes and CKD, respectively. The rate for recurrent CVD events per 1000 person-years was 135 among patients with prior CVD and 110, 124 and 171 among those with diabetes only, CKD only and both diabetes and CKD, respectively. Compared to patients with prior CVD, the multivariable-adjusted hazard ratio for recurrent CVD events was 0.92 (95%CI 0.90-0.95), 0.89 (95%CI: 0.85-0.93), and 1.18 (95%CI: 1.14-1.22) among those with diabetes only, CKD only, and both diabetes and CKD, respectively.
Conclusion
Following MI, adults with both diabetes and CKD had a higher risk for recurrent CVD events compared to those with prior CVD without diabetes or CKD.



Cardiovasc Diabetol: 28 Feb 2021; 20:58
Hubbard D, Colantonio LD, Rosenson RS, Brown TM, ... Farkouh ME, Muntner P
Cardiovasc Diabetol: 28 Feb 2021; 20:58 | PMID: 33648518
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Abstract

Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study.

Gaborit B, Ancel P, Abdullah AE, Maurice F, ... Kober F, Dutour A
Background
Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D).
Methods
C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks.
Results
In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and β-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups).
Conclusions
EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.



Cardiovasc Diabetol: 28 Feb 2021; 20:57
Gaborit B, Ancel P, Abdullah AE, Maurice F, ... Kober F, Dutour A
Cardiovasc Diabetol: 28 Feb 2021; 20:57 | PMID: 33648515
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Abstract

MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics.

Jakubik D, Fitas A, Eyileten C, Jarosz-Popek J, ... De Rosa S, Postula M
The epidemic of diabetes mellitus (DM) necessitates the development of novel therapeutic and preventative strategies to attenuate complications of this debilitating disease. Diabetic cardiomyopathy (DCM) is a frequent disorder affecting individuals diagnosed with DM characterized by left ventricular hypertrophy, diastolic and systolic dysfunction and myocardial fibrosis in the absence of other heart diseases. Progression of DCM is associated with impaired cardiac insulin metabolic signaling, increased oxidative stress, impaired mitochondrial and cardiomyocyte calcium metabolism, and inflammation. Various non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), as well as their target genes are implicated in the complex pathophysiology of DCM. It has been demonstrated that miRNAs and lncRNAs play an important role in maintaining homeostasis through regulation of multiple genes, thus they attract substantial scientific interest as biomarkers for diagnosis, prognosis and as a potential therapeutic strategy in DM complications. This article will review the different miRNAs and lncRNA studied in the context of DM, including type 1 and type 2 diabetes and the contribution of pathophysiological mechanisms including inflammatory response, oxidative stress, apoptosis, hypertrophy and fibrosis to the development of DCM .



Cardiovasc Diabetol: 26 Feb 2021; 20:55
Jakubik D, Fitas A, Eyileten C, Jarosz-Popek J, ... De Rosa S, Postula M
Cardiovasc Diabetol: 26 Feb 2021; 20:55 | PMID: 33639953
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Abstract

Traditional and non-traditional risk factors for peripheral artery disease development/progression in patients with type 2 diabetes: the Rio de Janeiro type 2 diabetes cohort study.

Cardoso CRL, Melo JV, Santos TRM, Leite NC, Salles GF
Background
The prognostic importance of non-traditional risk factors for peripheral artery disease (PAD) development/progression is scarcely studied in diabetes. We investigated if carotid intima-media thickness (CIMT) and carotid-femoral pulse wave velocity (cf-PWV) added prognostic information beyond traditional cardiovascular risk markers for PAD outcomes.
Methods
Ankle-brachial index (ABI) was measured at baseline and after a median of 91 months of follow-up in 681 individuals with type 2 diabetes. Multivariate Cox regressions examined the associations between the candidate variables and the outcome. PAD development/progression was defined by a reduction in ABI ≥ 0.15 (to a level < 0.9) or limb revascularization procedures, lower-extremity amputations or death due to PAD. The improvement in risk discrimination was assessed by increases in C-statistics of the models.
Results
Seventy-seven patients developed/progressed PAD: 50 reduced ABI to < 0.9, seven had lower-limb revascularizations, and 20 had amputations or death. Age, male sex, diabetes duration, presence of microvascular complications (peripheral neuropathy and diabetic kidney disease), baseline HbA1c, 24-h systolic BP (SBP) and mean cumulative office SBP and LDL-cholesterol were associated with PAD development/progression in several models. CIMT and cf-PWV were additionally associated with PAD outcomes, and their inclusion further improved risk discrimination (with C-statistic increases between 0.025 and 0.030). The inclusion of ambulatory 24-h SBP, instead of office SBP, also improved PAD risk discrimination.
Conclusions
Increased CIMT and aortic stiffness are associated with greater risks of developing/progressing PAD, beyond traditional risk factors, in type 2 diabetes.



Cardiovasc Diabetol: 26 Feb 2021; 20:54
Cardoso CRL, Melo JV, Santos TRM, Leite NC, Salles GF
Cardiovasc Diabetol: 26 Feb 2021; 20:54 | PMID: 33639945
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Abstract

Clinical and metabolomic predictors of regression to normoglycemia in a population at intermediate cardiometabolic risk.

Sevilla-González MDR, Merino J, Moreno-Macias H, Rojas-Martínez R, Gómez-Velasco DV, Manning AK
Background
Impaired fasting glucose (IFG) is a prevalent and potentially reversible intermediate stage leading to type 2 diabetes that increases risk for cardiometabolic complications. The identification of clinical and molecular factors associated with the reversal, or regression, from IFG to a normoglycemia state would enable more efficient cardiovascular risk reduction strategies. The aim of this study was to identify clinical and biological predictors of regression to normoglycemia in a non-European population characterized by high rates of type 2 diabetes.
Methods
We conducted a prospective, population-based study among 9637 Mexican individuals using clinical features and plasma metabolites. Among them, 491 subjects were classified as IFG, defined as fasting glucose between 100 and 125 mg/dL at baseline. Regression to normoglycemia was defined by fasting glucose less than 100 mg/dL in the follow-up visit. Plasma metabolites were profiled by Nuclear Magnetic Resonance. Multivariable cox regression models were used to examine the associations of clinical and metabolomic factors with regression to normoglycemia. We assessed the predictive capability of models that included clinical factors alone and models that included clinical factors and prioritized metabolites.
Results
During a median follow-up period of 2.5 years, 22.6% of participants (n = 111) regressed to normoglycemia, and 29.5% progressed to type 2 diabetes (n = 145). The multivariate adjusted relative risk of regression to normoglycemia was 1.10 (95% confidence interval [CI] 1.25 to 1.32) per 10 years of age increase, 0.94 (95% CI 0.91-0.98) per 1 SD increase in BMI, and 0.91 (95% CI 0.88-0.95) per 1 SD increase in fasting glucose. A model including information from age, fasting glucose, and BMI showed a good prediction of regression to normoglycemia (AUC = 0.73 (95% CI 0.66-0.78). The improvement after adding information from prioritized metabolites (TG in large HDL, albumin, and citrate) was non-significant (AUC = 0.74 (95% CI 0.68-0.80), p value = 0.485).
Conclusion
In individuals with IFG, information from three clinical variables easily obtained in the clinical setting showed a good prediction of regression to normoglycemia beyond metabolomic features. Our findings can serve to inform and design future cardiovascular prevention strategies.



Cardiovasc Diabetol: 26 Feb 2021; 20:56
Sevilla-González MDR, Merino J, Moreno-Macias H, Rojas-Martínez R, Gómez-Velasco DV, Manning AK
Cardiovasc Diabetol: 26 Feb 2021; 20:56 | PMID: 33639941
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Abstract

Thromboembolism, bleeding and vascular death in nonvalvular atrial fibrillation patients with type 2 diabetes receiving rivaroxaban or warfarin.

Coleman CI, Costa OS, Brescia CW, Vardar B, Abdelgawwad K, Sood N
Background
Diabetes increases a patient\'s risk of developing atrial fibrillation by 49%. Patients with nonvalvular atrial fibrillation are at a fivefold increased risk of stroke and die more frequently from vascular causes. We sought to evaluate the effectiveness and safety of rivaroxaban versus warfarin in nonvalvular atrial fibrillation patients with type 2 diabetes.
Methods
This was an analysis of Optum® De-Identified electronic health record data from 11/2010 to 12/2019. We included adults with nonvalvular atrial fibrillation and type 2 diabetes, newly started on rivaroxaban or warfarin and with ≥ 12-months of prior electronic health record activity. Patients who were pregnant, had alternative indications for oral anticoagulation or valvular heart disease were excluded. We evaluated the incidence rate (%/year) of developing the composite outcome of stroke/systemic embolism or vascular death and major or clinically relevant nonmajor bleeding as well as each endpoint individually. Hazard ratios with 95% confidence intervals were calculated using propensity score-overlap weighted proportional hazards regression.
Results
We included 32,078 rivaroxaban (31% initiated on 15 mg dose) and 83,971warfarin users (time-in-therapeutic range = 47 ± 28%). Rivaroxaban was associated with a reduced risk of stroke/systemic embolism or vascular death (3.79 vs. 4.19; hazard ratio = 0.91, 95% confdience interval = 0.88-0.95), driven mostly by reductions in vascular death (2.81 vs 3.18, hazard ratio = 0.90, 95% confidence interval = 0.86-0.95) and systemic embolism (0.13 vs. 0.16; hazard ratio = 0.82, 95% confidence interval = 0.66-1.02). Major/clinically relevant nonmajor bleeding was less frequent with rivaroxaban versus warfarin (2.17 vs. 2.31; hazard ratio = 0.94, 95% confidence interval = 0.89-0.99) due to decreased critical organ bleeding (including intracranial hemorrhage) (0.35 vs. 0.54; hazard ratio = 0.63, 95% confidence interval = 0.55-0.72).
Conclusions
In nonvalvular atrial fibrillation patients with type 2 diabetes, rivaroxaban was associated with an ~ 10% relative reduction in vascular mortality and fewer bleeding-related hospitalizations versus warfarin.



Cardiovasc Diabetol: 25 Feb 2021; 20:52
Coleman CI, Costa OS, Brescia CW, Vardar B, Abdelgawwad K, Sood N
Cardiovasc Diabetol: 25 Feb 2021; 20:52 | PMID: 33637082
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Abstract

Activation of the cardiac non-neuronal cholinergic system prevents the development of diabetes-associated cardiovascular complications.

Saw EL, Pearson JT, Schwenke DO, Munasinghe PE, ... Fronius M, Katare R
Background
Acetylcholine (ACh) plays a crucial role in the function of the heart. Recent evidence suggests that cardiomyocytes possess a non-neuronal cholinergic system (NNCS) that comprises of choline acetyltransferase (ChAT), choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), acetylcholinesterase (AChE) and type-2 muscarinic ACh receptors (M2AChR) to synthesize, release, degrade ACh as well as for ACh to transduce a signal. NNCS is linked to cardiac cell survival, angiogenesis and glucose metabolism. Impairment of these functions are hallmarks of diabetic heart disease (DHD). The role of the NNCS in DHD is unknown. The aim of this study was to examine the effect of diabetes on cardiac NNCS and determine if activation of cardiac NNCS is beneficial to the diabetic heart.
Methods
Ventricular samples from type-2 diabetic humans and db/db mice were used to measure the expression pattern of NNCS components (ChAT, CHT1, VAChT, AChE and M2AChR) and glucose transporter-4 (GLUT-4) by western blot analysis. To determine the function of the cardiac NNCS in the diabetic heart, a db/db mouse model with cardiac-specific overexpression of ChAT gene was generated (db/db-ChAT-tg). Animals were followed up serially and samples collected at different time points for molecular and histological analysis of cardiac NNCS components and prosurvival and proangiogenic signaling pathways.
Results
Immunoblot analysis revealed alterations in the components of cardiac NNCS and GLUT-4 in the type-2 diabetic human and db/db mouse hearts. Interestingly, the dysregulation of cardiac NNCS was followed by the downregulation of GLUT-4 in the db/db mouse heart. Db/db-ChAT-tg mice exhibited preserved cardiac and vascular function in comparison to db/db mice. The improved function was associated with increased cardiac ACh and glucose content, sustained angiogenesis and reduced fibrosis. These beneficial effects were associated with upregulation of the PI3K/Akt/HIF1α signaling pathway, and increased expression of its downstream targets-GLUT-4 and VEGF-A.
Conclusion
We provide the first evidence for dysregulation of the cardiac NNCS in DHD. Increased cardiac ACh is beneficial and a potential new therapeutic strategy to prevent or delay the development of DHD.



Cardiovasc Diabetol: 21 Feb 2021; 20:50
Saw EL, Pearson JT, Schwenke DO, Munasinghe PE, ... Fronius M, Katare R
Cardiovasc Diabetol: 21 Feb 2021; 20:50 | PMID: 33618724
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Abstract

Prognostic value of soluble suppression of tumorigenesis-2 (sST2) for cardiovascular events in coronary artery disease patients with and without diabetes mellitus.

Li M, Duan L, Cai Y, Hao B, ... Li H, Liu H
Background
Soluble suppression of tumorigenesis-2 (sST2) is implicated in myocardial overload and has long been recognized as an inflammatory marker related to heart failure and acute coronary syndrome, but data on the prognostic value of sST2 in patients with coronary artery disease (CAD) remain limited. This study sought to investigate the prognostic value of sST2 in patients with established CAD and its predictive value in CAD patients with and without type 2 diabetes mellitus (T2DM).
Methods
A total of 3641 consecutive patients were included in this prospective cohort study. The primary end point was major adverse cardiovascular events (MACEs). The secondary end point was all-cause death. The association between sST2 and outcomes was investigated using multivariable Cox regression.
Results
During a median follow-up of 6.4 years, MACEs occurred in 775 patients, and 275 patients died. Multiple Cox regression models showed that a higher level of sST2 was an independent predictor of MACEs development (HR = 1.36, 95% CI 1.17-1.56, p < 0.001) and all-cause death (HR = 2.01, 95% CI 1.56-2.59, p < 0.001). The addition of sST2 to established risk factors significantly improved risk prediction of the composite outcome of MACEs and all-cause death (C-index, net reclassification index, and integrated discrimination improvement, all p < 0.05). In subgroup analysis depending on diabetes status, the diabetes group had a significantly higher level of sST2, which remained a significant predictor of MACEs and all-cause death in patients with and without T2DM in multivariable models. The area under the curve (AUC) of CAD patients with diabetes mellitus was significantly higher than that of those without T2DM. For MACEs, the AUC was 0.737 (patients with T2DM) vs 0.620 (patients without T2DM). For all-cause death, the AUC was 0.923 (patients with T2DM) vs 0.789 (patients without T2DM).
Conclusions
A higher level of sST2 is significantly associated with long-term MACEs and all-cause death in CAD patients with and without T2DM. sST2 has strong predictive value for cardiovascular adverse events in CAD patients with T2DM, and these results provide new evidence for the role of sST2.



Cardiovasc Diabetol: 18 Feb 2021; 20:49
Li M, Duan L, Cai Y, Hao B, ... Li H, Liu H
Cardiovasc Diabetol: 18 Feb 2021; 20:49 | PMID: 33608010
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Abstract

Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort.

Lejeune S, Roy C, Slimani A, Pasquet A, ... Beauloye C, Pouleur AC
Background
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C).
Methods
We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves.
Results
Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m2, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m2, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients. Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1-2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1-4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels).
Conclusion
Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.



Cardiovasc Diabetol: 18 Feb 2021; 20:48
Lejeune S, Roy C, Slimani A, Pasquet A, ... Beauloye C, Pouleur AC
Cardiovasc Diabetol: 18 Feb 2021; 20:48 | PMID: 33608002
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Abstract

Plasma fibrin clot properties and cardiovascular mortality in patients with type 2 diabetes: a long-term follow-up study.

Bryk AH, Konieczyńska M, Polak M, Plicner D, Bochenek M, Undas A
Background
Patients with type 2 diabetes mellitus (T2DM) are at high risk of cardiovascular mortality, but the mechanisms behind this remain unclear. Prothrombotic fibrin clot properties have been shown in T2DM and cardiovascular disease. We hypothesized that formation of denser clots, which are resistant to fibrinolysis, has a negative impact on cardiovascular mortality in T2DM.
Methods
We studied 133 T2DM patients aged 43-83 years. Plasma fibrin clot turbidity, permeation, compaction, and efficiency of clot lysis using 3 assays including the determination of maximum concentration (D-Dmax) and rate of increase in D-dimer concentration (D-Drate) released during tissue plasminogen activator-induced degradation, were evaluated at the time of enrollment, along with thrombin generation and fibrinolytic proteins. During a median follow-up period of 72 months, cardiovascular mortality was recorded.
Results
Cardiovascular deaths (n = 16, 12%) occurred more frequently in patients with increased D-Dmax (> 4.26 mg/l, hazard ratio [HR] 5.43, 95% confidence interval [CI] 1.99-14.79), or decreased D-Drate (< 0.07 mg/l/min, HR 2.97, 95% CI 1.07-8.23), or increased peak thrombin (> 283.5 nM, HR 5.65, 95% CI 2.07-15.51). These predictors had an even more potent impact on cardiovascular mortality in patients with prior cardiovascular disease (64.7%) and with corresponding risks as follows: HR 6.18, 95% CI 2.02-18.96; HR 8.98, 95% CI 2.99-26.96; and HR 5.35, 95% CI 1.62-17.72, respectively. Other investigated fibrin variables and fibrinolytic proteins did not associate with cardiovascular mortality. In multivariable analysis, cardiovascular mortality was predicted by D-Dmax > 4.26 mg/l, age > 65 years, prior cardiovascular disease, and C-reactive protein > 3 mg/l.
Conclusions
This study is the first to show that formation of denser fibrin clots resistant to fibrinolysis could be a risk factor for long-term cardiovascular mortality in T2DM.



Cardiovasc Diabetol: 17 Feb 2021; 20:47
Bryk AH, Konieczyńska M, Polak M, Plicner D, Bochenek M, Undas A
Cardiovasc Diabetol: 17 Feb 2021; 20:47 | PMID: 33602240
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Abstract

Triglyceride-glucose index and the risk of stroke and its subtypes in the general population: an 11-year follow-up.

Wang A, Wang G, Liu Q, Zuo Y, ... Wang Y, Wang Y
Background
Triglyceride-glucose (TyG) index was recently suggested to be a reliable surrogate marker of insulin resistance. We aim to investigate the associations between baseline and long-term TyG index with subsequent stroke and its subtypes in a community-based cohort.
Methods
A total of 97,653 participants free of history of stroke in the Kailuan Study were included. TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). Baseline TyG index was measured during 2006-2007. Updated cumulative average TyG index used all available TyG index from baseline to the outcome events of interest or the end of follow up. The outcome was the first occurrence of stroke, including ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage. The associations of TyG index with outcomes were explored with Cox regression.
Results
During a median of 11.02 years of follow-up, 5122 participants developed stroke of whom 4277 were ischemic stroke, 880 intracerebral hemorrhage, and 144 subarachnoid hemorrhage. After adjusting for confounding variables, compared with participants in the lowest quartile of baseline TyG index, those in the third and fourth quartile were associated with an increased risk of stroke (adjusted hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.12-1.33, and adjusted HR 1.32, 95% CI 1.21-1.44, respectively, P for trend < 0.001). We also found a linear association between baseline TyG index with stroke. Similar results were found for ischemic stroke. However, no significant associations were observed between baseline TyG index and risk of intracranial hemorrhage. Parallel results were observed for the associations of updated cumulative average TyG index with outcomes.
Conclusions
Elevated levels of both baseline and long-term updated cumulative average TyG index can independently predict stroke and ischemic stroke but not intracerebral hemorrhage in the general population during an 11-year follow-up.



Cardiovasc Diabetol: 17 Feb 2021; 20:46
Wang A, Wang G, Liu Q, Zuo Y, ... Wang Y, Wang Y
Cardiovasc Diabetol: 17 Feb 2021; 20:46 | PMID: 33602208
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Abstract

Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes.

Nandula SR, Kundu N, Awal HB, Brichacek B, ... Amdur RL, Sen S
Background
Endothelial progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Effect of sodium glucose channel inhibitors (SGLT2i) such as Canagliflozin (CG) on a cellular biomarker such as CD34+ve progenitor cells, which may help predict CVD risk, in patients with T2DM with established CKD has not been explored.
Methods
This is a pilot study where 29 subjects taking metformin and/or Insulin were enrolled in a 16 week, double blind, randomized placebo matched trial, with a low dose 100 mg CG as the intervention group compared to matched placebo. Type 2 diabetes subjects (30-70 years old), with hemoglobin A1c (HbA1c) of 7-10%, were enrolled. CD34+ve cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, serum biochemistry pertaining to cardio-metabolic health, resting energy expenditure and body composition were measured. Data were collected at week 0, 8 and 16. A mixed model regression analysis was done and p value less than 0.05 was considered statistically significant.
Results
A significant expression of CXCR4 receptor with a concomittant increase in migratory function of CD34+ve cells was observed in CG treated group as compared to placebo group. Gene expression analysis of CD34+ve cells showed an increase in expression of antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and notable endothelial markers (PECAM1, VEGF-A, and NOS3). A significant reduction in glucose and HbA1c levels were observed along with improved systolic and diastolic blood pressure in the CG group. A significant increase in adiponectin (p = 0.006) was also noted in treatment group. Urinary exosomal protein leak in urine, examining podocyte health (podocalyxin, Wilm\'s tumor and nephrin) showed reduction with CG
Conclusion:
Low dose Canagliflozin has a beneficial effect on CD34+ cell function, serum biochemistry and urinary podocyte specific exosomes in type 2 diabetes.



Cardiovasc Diabetol: 12 Feb 2021; 20:44
Nandula SR, Kundu N, Awal HB, Brichacek B, ... Amdur RL, Sen S
Cardiovasc Diabetol: 12 Feb 2021; 20:44 | PMID: 33581737
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Abstract

The predictive utility of circulating PCSK9 levels on diabetes mellitus.

Peng J, Zhu CG, Li JJ
Increasing data including ours have suggested that proprotein convertase subtilisin/kexin type 9 (PCSK9), a novel regulator of cholesterol metabolism, may also play an important role in the development of type 2 diabetes mellitus (T2DM) and is associated with clinical outcomes in diabetic patients. Previous studies revealed that elevated plasma PCSK9 levels had a higher incidence of new-onset T2DM. Moreover, the results of available epidemiological, preclinical, and clinical studies have indicated that plasma PCSK9 concentration is correlated with glycemic parameters and can predict the adverse cardiovascular events in diabetic patients with coronary artery disease. However, there is currently no general agreement about the association of PCSK9 with T2DM. The usefulness of the circulating PCSK9 concentration as a predictor for the risk of new-onset T2DM should be clinically prudential.



Cardiovasc Diabetol: 12 Feb 2021; 20:45
Peng J, Zhu CG, Li JJ
Cardiovasc Diabetol: 12 Feb 2021; 20:45 | PMID: 33581713
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Abstract

Cardiovascular surrogate markers and cardiometabolic therapeutics: a viewpoint learned from clinical trials on dipeptidyl peptidase-4 inhibitors.

Tanaka A, Node K
Clinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular function and biomarkers. This study platform has the potential to provide information on the suspected actions of drugs and mechanistic insights into their prognostic impact. However, despite using the same class of drugs and similar study designs we are often faced with inconsistent and even conflicting results, possibly leading to some confusion in the clinical setting. When interpreting these results, it is important to investigate what caused the differences and carefully assess the information, taking into account the research situation and the patient population investigated. Using this approach, assessment of the impact on cardiovascular surrogate markers observed in clinical studies from multiple perspectives should help to better understand the potential cardiovascular effects. In this commentary we discuss how we should interpret the effects of cardiometabolic therapeutics on vascular surrogate markers, based on viewpoints learned from the results of clinical trials on dipeptidyl peptidase-4 inhibitors. This learning strategy could also be helpful for appropriate selection of drugs for evidence-based, patient-centric, tailored medication.



Cardiovasc Diabetol: 10 Feb 2021; 20:41
Tanaka A, Node K
Cardiovasc Diabetol: 10 Feb 2021; 20:41 | PMID: 33573675
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Abstract

SGLT-2 inhibitors and atrial fibrillation in the Food and Drug Administration adverse event reporting system.

Bonora BM, Raschi E, Avogaro A, Fadini GP
Background
Sodium glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of heart failure and new data show they can prevent atrial fibrillation (AF). We examined the association between SGLT2i and AF in the Food and Drug Administration adverse event reporting system (FAERS).
Methods
We mined the FAERS from 2014q1 to 2019q4 to compare AF reporting for SGLT-2 i versus reports for other glucose lowering medications (ATC10 class). Several exclusions were sequentially applied for: concomitant medications; diabetes, cardiovascular or renal disease indication; reports for competing adverse events (genitourinary tract infections, ketoacidosis, Fournier\'s gangrene, amputation). We provide descriptive statistics and calculated proportional reporting ratios (PRR).
Results
There were 62,098 adverse event reports for SGLT2i and 642,031 reports for other ATC10 drugs. The reporting of AF was significantly lower with SGLT2i than with other ATC10 drugs (4.8 versus 8.7/1000; p < 0.001) with a PRR of 0.55 (0.49-0.62). Results did not change substantially after excluding reports listing insulin (PRR 0.49) or anti-arrhythmics (PRR 0.59) as suspect or concomitant drugs, excluding reports with indications for cardiovascular disease (PRR 0.49) or renal disease (PRR 0.55), and those filed for competing adverse events (PRR 0.63). Results were always statistically significant whether the diabetes indication was specified. Negative and positive controls confirmed internal validity of the database.
Conclusions
In a large pharmacovigilance database, AF was robustly and consistently reported more frequently for diabetes medications other than SGLT2i. This finding complements available evidence from trials supporting a protective role of SGLT2i against the occurrence of AF.



Cardiovasc Diabetol: 10 Feb 2021; 20:39
Bonora BM, Raschi E, Avogaro A, Fadini GP
Cardiovasc Diabetol: 10 Feb 2021; 20:39 | PMID: 33573667
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Abstract

Prognostic significance of diabetes mellitus in patients with atrial fibrillation.

Papazoglou AS, Kartas A, Samaras A, Vouloagkas I, ... Tzikas A, Giannakoulas G
Background
There are limited data on the association of diabetes mellitus (DM) and levels of glycated hemoglobin (HbA1c) with outcomes in patients with atrial fibrillation (AF).
Methods
This retrospective cohort study included patients who were recently hospitalized with a primary or secondary diagnosis of AF from December 2015 through June 2018. Kaplan-Meier curves and Cox-regression adjusted hazard ratios (aHR) were calculated for the primary outcome of all-cause mortality and for the secondary outcomes of cardiovascular (CV) mortality and the composite outcome of CV death or hospitalization. Competing-risk regression analyses were performed to calculate the cumulative risk of stroke, major bleeding, AF- or HF-hospitalizations adjusted for the competing risk of all-cause death. Spline curve models were fitted to investigate associations of HbA1c values and mortality among patients with AF and DM.
Results
In total 1109 AF patients were included, of whom 373 (33.6%) had DM. During a median follow-up of 2.6 years, 414 (37.3%) patients died. The presence of DM was associated with a higher risk of all-cause mortality (aHR = 1.40 95% confidence intervals [CI] 1.11-1.75), CV mortality (aHR = 1.39, 95% CI 1.07-1.81), sudden cardiac death (aHR = 1.73, 95% CI 1.19-2.52), stroke (aHR = 1.87, 95% CI 1.01-3.45) and the composite outcome of hospitalization or CV death (aHR = 1.27, 95% CI 1.06-1.53). In AF patients with comorbid DM, the spline curves showed a positive linear association between HbA1c levels and outcomes, with values 7.6-8.2% being independent predictors of increased all-cause mortality, and values < 6.2% predicting significantly decreased all-cause and CV mortality.
Conclusions
The presence of DM on top of AF was associated with substantially increased risk for all-cause or CV mortality, sudden cardiac death and excess morbidity. HbA1c levels lower than 6.2% were independently related to better survival rates suggesting that optimal DM control could be associated with better clinical outcomes in AF patients with DM.



Cardiovasc Diabetol: 10 Feb 2021; 20:40
Papazoglou AS, Kartas A, Samaras A, Vouloagkas I, ... Tzikas A, Giannakoulas G
Cardiovasc Diabetol: 10 Feb 2021; 20:40 | PMID: 33573666
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Abstract

Gender differences in screening for glucose perturbations, cardiovascular risk factor management and prognosis in patients with dysglycaemia and coronary artery disease: results from the ESC-EORP EUROASPIRE surveys.

Ferrannini G, De Bacquer D, Vynckier P, De Backer G, ... Rydén L, EUROASPIRE IV & V Investigators
Background
Gender disparities in the management of dysglycaemia, defined as either impaired glucose tolerance (IGT) or type 2 diabetes (T2DM), in coronary artery disease (CAD) patients are a medical challenge. Recent data from two nationwide cohorts of patients suggested no gender difference as regards the risk for diabetes-related CV complications but indicated the presence of a gender disparity in risk factor management. The aim of this study was to investigate gender differences in screening for dysglycaemia, cardiovascular risk factor management and prognosis in dysglycemic CAD patients.
Methods
The study population (n = 16,259; 4077 women) included 7998 patients from the ESC-EORP EUROASPIRE IV (EAIV: 2012-2013, 79 centres in 24 countries) and 8261 patients from the ESC-EORP EUROASPIRE V (EAV: 2016-2017, 131 centres in 27 countries) cross-sectional surveys. In each centre, patients were investigated with standardised methods by centrally trained staff and those without known diabetes were offered an oral glucose tolerance test (OGTT). The first of CV death or hospitalisation for non-fatal myocardial infarction, stroke, heart failure or revascularization served as endpoint. Median follow-up time was 1.7 years. The association between gender and time to the occurrence of the endpoint was evaluated using Cox survival modelling, adjusting for age.
Results
Known diabetes was more common among women (32.9%) than men (28.4%, p < 0.0001). OGTT (n = 8655) disclosed IGT in 17.2% of women vs. 15.1% of men (p = 0.004) and diabetes in 13.4% of women vs. 14.6% of men (p = 0.078). In both known diabetes and newly detected dysglycaemia groups, women were older, with higher proportions of hypertension, dyslipidaemia and obesity. HbA1c was higher in women with known diabetes. Recommended targets of physical activity, blood pressure and cholesterol were achieved by significantly lower proportions of women than men. Women with known diabetes had higher risk for the endpoint than men (age-adjusted HR 1.22; 95% CI 1.04-1.43).
Conclusions
Guideline-recommended risk factor control is poorer in dysglycemic women than men. This may contribute to the worse prognosis in CAD women with known diabetes.



Cardiovasc Diabetol: 10 Feb 2021; 20:38
Ferrannini G, De Bacquer D, Vynckier P, De Backer G, ... Rydén L, EUROASPIRE IV & V Investigators
Cardiovasc Diabetol: 10 Feb 2021; 20:38 | PMID: 33573665
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Abstract

Predictive effect of triglyceride‑glucose index on clinical events in patients with type 2 diabetes mellitus and acute myocardial infarction: results from an observational cohort study in China.

Zhang Y, Ding X, Hua B, Liu Q, ... Li W, Li H
Background
Triglyceride glucose (TyG) index is considered a reliable alternative marker of insulin resistance and an independent predictor of cardiovascular (CV) outcomes. However, the prognostic value of TyG index in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction (AMI) remains unclear.
Methods
A total of 1932 consecutive patients with T2DM and AMI were enrolled in this study. Patients were divided into tertiles according to their TyG index levels. The incidence of major adverse cardiac and cerebral events (MACCEs) was recorded. The TyG index was calculated as the ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2].
Results
Competing risk regression revealed that the TyG index was positively associated with CV death [2.71(1.92 to 3.83), p < 0.001], non-fatal MI [2.02(1.32 to 3.11), p = 0.001], cardiac rehospitalization [2.42(1.81 to 3.24), p < 0.001], revascularization [2.41(1.63 to 3.55), p < 0.001] and composite MACCEs [2.32(1.92 to 2.80), p < 0.001]. The area under ROC curve of the TyG index for predicting the occurrence of MACCEs was 0.604 [(0.578 to 0.630), p < 0.001], with the cut-off value of 9.30. The addition of TyG index to a baseline risk model had an incremental effect on the predictive value for MACCEs [net reclassification improvement (NRI): 0.190 (0.094 to 0.337); integrated discrimination improvement (IDI): 0.027 (0.013 to 0.041); C-index: 0.685 (0.663 to 0.707), all p < 0.001].
Conclusions
The TyG index was significantly associated with MACCEs, suggesting that the TyG index may be a valid marker for risk stratification and prognosis in patients with T2DM and AMI. Trial registration Retrospectively registered.



Cardiovasc Diabetol: 10 Feb 2021; 20:43
Zhang Y, Ding X, Hua B, Liu Q, ... Li W, Li H
Cardiovasc Diabetol: 10 Feb 2021; 20:43 | PMID: 33573649
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Abstract

Treatment strategies in patients with diabetes and three-vessel coronary disease: What should we choose?

Liang B, Gu N
The recent study demonstrating that percutaneous coronary intervention and coronary artery bypass grafting were associated with a lower risk of death and major adverse cardiac and cerebrovascular events (composite of all-cause death, myocardial infarction, or stroke) than with medical therapy among patients with diabetes and triple-vessel disease was very interesting. However, the nature of single-center nonrandomized and nonblinded studies that are not placebo controlled limits the extrapolation and generalizability of the results. As a result, the existing body of evidence does not fully support the use of revascularization treatment strategies in patients with diabetes and triple-vessel disease. Importantly, the safety of revascularization treatment strategies in this particular population remains uncertain. Therefore, further studies are needed to assess the risks and benefits of comprehensive treatment in these patients.



Cardiovasc Diabetol: 10 Feb 2021; 20:42
Liang B, Gu N
Cardiovasc Diabetol: 10 Feb 2021; 20:42 | PMID: 33573627
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Abstract

Epicardial adipose tissue volume and coronary calcification among people living with diabetes: a cross-sectional study.

Cosson E, Nguyen MT, Rezgani I, Tatulashvili S, ... Brillet PY, Bihan H
Background
Epicardial adipose tissue (EAT) has anatomic and functional proximity to the heart and is considered a novel diagnostic marker and therapeutic target in cardiometabolic diseases. The aim of this study was to evaluate whether EAT volume was associated with coronary artery calcification (CAC) in people living with diabetes, independently of confounding factors.
Methods
We included all consecutive patients with diabetes whose EAT volume and CAC score were measured using computed tomography between January 1, 2019 and September 30, 2020 in the Department of Diabetology-Endocrinology-Nutrition at Avicenne Hospital, France. Determinants of EAT volume and a CAC score ≥ 100 Agatston units (AU) were evaluated.
Results
The study population comprised 409 patients (218 men). Mean (± standard deviation) age was 57 ± 12 years, and 318, 56 and 35 had type 2 (T2D), type 1 (T1D), or another type of diabetes, respectively. Mean body mass index (BMI) was 29 ± 6 kg/m2, mean AET volume 93 ± 38 cm3. EAT volume was positively correlated with age, BMI, pack-year smoking history and triglyceridaemia, but negatively correlated with HDL-cholesterol level. Furthermore, it was lower in people with retinopathy, but higher in men, in Caucasian people, in patients on antihypertensive and lipid-lowering medication, in people with nephropathy, and finally in individuals with a CAC ≥ 100 AU (CAC < 100 vs CAC ≥ 100: 89 ± 35 vs 109 ± 41 cm3, respectively, p < 0.05). In addition to EAT volume, other determinants of CAC ≥ 100 AU (n = 89, 22%) were age, T2D, ethnicity, antihypertensive and lipid-lowering medication, cumulative tobacco consumption, retinopathy, macular edema and macrovascular disease. Multivariable analysis considering all these determinants as well as gender and BMI showed that EAT volume was independently associated with CAC ≥ 100 AU (per 10 cm3 increase: OR 1.11 [1.02-1.20]).
Conclusions
EAT volume was independently associated with CAC. As it may play a role in coronary atherosclerosis in patients with diabetes, reducing EAT volume through physical exercise, improved diet and pharmaceutical interventions may improve future cardiovascular risk outcomes in this population.



Cardiovasc Diabetol: 04 Feb 2021; 20:35
Cosson E, Nguyen MT, Rezgani I, Tatulashvili S, ... Brillet PY, Bihan H
Cardiovasc Diabetol: 04 Feb 2021; 20:35 | PMID: 33546697
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Abstract

The residual cardiorenal risk in type 2 diabetes.

Giugliano D, Maiorino MI, Bellastella G, Esposito K
In this commentary, we introduce the concepts of removed and residual risks in conditioning thecardiorenal outlook of patients with type 2 diabetes (T2D). The removed cardiorenal risk represents the risk of progression of CV events (major adverse cardiovascular events, MACE; heart failure, HF) and diabetes kidney disease (DKD) taken away by optimal glycemic control or the use of newer antihyperglycemic drugs (glucagon-like peptide-1 receptor agonists, GLP-1RA, andsodium-glucose transporter-2 inhibitors, SGLT-2i) in patients with T2D, as demonstrated by the results of intensive glucose lowering trials (IGT) and cardiovascular outcome trials (CVOT). IGT have shown that successful glycemic control has modest benefits, as the removed cardiorenal risk ranges from 9% for MACE, to 20% for progression of DKD and to 0% for HF. The removed risk of MACE is 13% for GLP-1RA and 12% for SGLT-2i. However, SGLT-2i, as compared with GLP-1RA, removed twofold more risk (39% vs 17%) for kidney outcomes and fourfold more risk (33% vs 9%) for HF. Dipeptidyl peptidase-4 inhibitors have no clinically important cardiorenal benefits, as residual risk is 99% for MACE, 100% for kidney outcomes (excluding new albuminuria), and 100% for HF. Although the results of some real world, population-based cohort studies suggest the possibility that the cardiorenal protection afforded by newer antihyperglycemic drugs is additive to that of optimal glycemic control, only specific randomized controlled trials could answer this question.



Cardiovasc Diabetol: 04 Feb 2021; 20:36
Giugliano D, Maiorino MI, Bellastella G, Esposito K
Cardiovasc Diabetol: 04 Feb 2021; 20:36 | PMID: 33546683
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Abstract

Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus.

Prausmüller S, Resl M, Arfsten H, Spinka G, ... Clodi M, Hülsmann M
Background
Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM).
Methods and results
A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups.
Conclusion
The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.



Cardiovasc Diabetol: 01 Feb 2021; 20:34
Prausmüller S, Resl M, Arfsten H, Spinka G, ... Clodi M, Hülsmann M
Cardiovasc Diabetol: 01 Feb 2021; 20:34 | PMID: 33530999
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Abstract

A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study.

Hiruma S, Shigiyama F, Hisatake S, Mizumura S, ... Hirose T, Kumashiro N
Background
While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications.
Methods
This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, 123I-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period.
Results
The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m2). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including β-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05).
Conclusions
Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications.
Clinical trial registration
UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257.



Cardiovasc Diabetol: 01 Feb 2021; 20:32
Hiruma S, Shigiyama F, Hisatake S, Mizumura S, ... Hirose T, Kumashiro N
Cardiovasc Diabetol: 01 Feb 2021; 20:32 | PMID: 33530982
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Abstract

Hyperglycemia, inflammatory response and infarct size in obstructive acute myocardial infarction and MINOCA.

Paolisso P, Foà A, Bergamaschi L, Donati F, ... Galiè N, Pizzi C
Background
Hyperglycemia has been associated with increased inflammatory indexes and larger infarct sizes in patients with obstructive acute myocardial infarction (obs-AMI). In contrast, no studies have explored these correlations in non-obstructive acute myocardial infarction (MINOCA). We investigated the relationship between hyperglycemia, inflammation and infarct size in a cohort of AMI patients that included MINOCA.
Methods
Patients with AMI undergoing coronary angiography between 2016 and 2020 were enrolled. The following inflammatory markers were evaluated: C-reactive protein, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and neutrophil-to-platelet ratio (NPR). Myocardial infarct size was measured by peak high sensitivity troponin I (Hs-TnI) levels, left-ventricular-end-diastolic-volume (LVEDV) and left ventricular ejection fraction (LVEF).
Results
The final study population consisted of 2450 patients with obs-AMI and 239 with MINOCA. Hyperglycemia was more prevalent among obs-AMI cases. In all hyperglycemic patients-obs-AMI and MINOCA-NLR, NPR, and LPR were markedly altered. Hyperglycemic obs-AMI subjects exhibited a higher Hs-TnI (p < 0.001), a larger LVEDV (p = 0.003) and a lower LVEF (p < 0.001) compared to normoglycemic ones. Conversely, MINOCA patients showed a trivial myocardial damage, irrespective of admission glucose levels.
Conclusions
Our data confirm the association of hyperglycemic obs-AMI with elevated inflammatory markers and larger infarct sizes. MINOCA patients exhibited modest myocardial damage, regardless of admission glucose levels.



Cardiovasc Diabetol: 01 Feb 2021; 20:33
Paolisso P, Foà A, Bergamaschi L, Donati F, ... Galiè N, Pizzi C
Cardiovasc Diabetol: 01 Feb 2021; 20:33 | PMID: 33530978
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Abstract

Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus.

Li T, Providencia R, Mu N, Yin Y, ... Gu C, Ma H
Background
Metformin is a first-line drug in type 2 diabetes mellitus (T2DM) treatment, yet whether metformin may increase all-cause or cardiovascular mortality of T2DM patients remains inconclusive.
Methods
We searched PubMed and Embase for data extracted from inception to July 14, 2020, with a registration in PROSPERO (CRD42020177283). This study included randomized controlled trials (RCT) assessing the cardiovascular effects of metformin for T2DM. This study is followed by PRISMA and Cochrane guideline. Risk ratio (RR) with 95% CI was pooled across trials by a random-effects model. Primary outcomes include all-cause mortality and cardiovascular mortality.
Results
We identified 29 studies that randomly assigned patients with 371 all-cause and 227 cardiovascular death events. Compared with untreated T2DM patients, metformin-treated patients was not associated with lower risk of all-cause mortality (RR: 0.98; 95%CI: 0.69-1.38; P = 0.90), cardiovascular mortality (RR: 1.13; 95% CI: 0.60, 2.15; P = 0.70), macrovascular events (RR: 0.87; 95%CI: 0.70-1.07; P = 0.19), heart failure (RR: 1.02; 95% CI:0.61-1.71; P = 0.95), and microvascular events (RR: 0.78; 95% CI:0.54-1.13; P = 0.19). Combination of metformin with another hypoglycemic drug was associated with higher risk of all-cause mortality (RR: 1.49; 95% CI: 1.02, 2.16) and cardiovascular mortality (RR: 2.21; 95% CI: 1.22, 4.00) compared with hypoglycemic drug regimens with no metformin.
Conclusion
The combination of metformin treatment may impose higher risk in all-cause and cardiovascular mortality. This finding, at least in part, shows no evidence for benefits of metformin in combination in terms of all-cause/cardiovascular mortality and cardiovascular events for T2DM. However, the conclusion shall be explained cautiously considering the limitations from UK Prospective Diabetes Study (UKPDS).



Cardiovasc Diabetol: 29 Jan 2021; 20:30
Li T, Providencia R, Mu N, Yin Y, ... Gu C, Ma H
Cardiovasc Diabetol: 29 Jan 2021; 20:30 | PMID: 33516224
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Impact:
Abstract

Independent association of atherogenic dyslipidaemia with all-cause mortality in individuals with type 2 diabetes and modifying effect of gender: a prospective cohort study.

Orsi E, Penno G, Solini A, Bonora E, ... Pugliese G, Renal Insufficiency And Cardiovascular Events (RIACE) Study Group
Background
Atherogenic dyslipidaemia has been implicated in the residual risk for cardiovascular morbidity and mortality, which remains despite attainment of LDL cholesterol goals especially in individuals with type 2 diabetes. However, its relationship with all-cause death has not been sufficiently explored. This analysis evaluated the independent association of increased triglycerides and triglyceride:HDL cholesterol ratio (TG:HDL) and decreased HDL cholesterol with total mortality and the possible modifying effect of gender in a large cohort of patients with type 2 diabetes.
Methods
This observational, prospective study enrolled 15,773 patients in 19 Diabetes Clinics throughout Italy in the years 2006-2008. Triglycerides and total and HDL cholesterol were measured by colorimetric enzymatic methods. Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%). Participants were stratified by quartiles of triglycerides, HDL cholesterol, and TG:HDL.
Results
There were 3,602 deaths over a follow-up 7.42 ± 2.05 years (31.0 × 1000 person-years). In the unadjusted analyses, the highest TG:HDL (but not triglyceride) and the lowest HDL cholesterol quartile were associated with increased death rate and mortality risk. When sequentially adjusting for confounders, including total, LDL, or non-HDL cholesterol and lipid-lowering treatment, mortality risk was significantly higher in the highest triglyceride (hazard ratio 1.167 [95% confidence interval 1.055-1.291], p = 0.003) and TG:HDL (1.192 [1.082-1.314], p < 0.0001) and the lowest HDL cholesterol (1.232 [1.117-1.360], p < 0.0001) quartile, though the association of triglycerides and HDL cholesterol disappeared after further adjustment for each other. Interaction with gender was significant only for HDL cholesterol (p = 0.0009). The relationship with death was stronger for triglycerides in males and HDL cholesterol in females, with these associations remaining significant even after adjustment for HDL cholesterol (1.161 [1.019-1.324], p = 0.025, for the highest vs the lowest triglyceride quartile) and triglycerides (1.366 [1.176-1.587], p < 0.0001, for the lowest vs the highest HDL cholesterol quartile).
Conclusions
In patients with type 2 diabetes, higher triglycerides and TG:HDL and lower HDL cholesterol were independently associated with increased all-cause mortality, with a modifying effect of gender for triglycerides and HDL cholesterol. These data suggest that atherogenic dyslipidaemia, especially TG:HDL, may serve as predictor of all-cause death in these individuals. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008.



Cardiovasc Diabetol: 29 Jan 2021; 20:28
Orsi E, Penno G, Solini A, Bonora E, ... Pugliese G, Renal Insufficiency And Cardiovascular Events (RIACE) Study Group
Cardiovasc Diabetol: 29 Jan 2021; 20:28 | PMID: 33516215
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Impact:
Abstract

Long-term prognosis of chronic total occlusion treated by successful percutaneous coronary intervention in patients with or without diabetes mellitus: a systematic review and meta-analysis.

Zhu Y, Meng S, Chen M, Liu K, ... Zhu H, Jin Z
Background
Diabetes mellitus (DM) is highly prevalent among patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). Therefore, the purpose of our study was to investigate the clinical outcomes of CTO-PCI in patients with or without DM.
Methods
All relevant articles published in electronic databases (PubMed, Embase, and the Cochrane Library) from inception to August 7, 2020 were identified with a comprehensive literature search. Additionally, we defined major adverse cardiac events (MACEs) as the primary endpoint and used risk ratios (RRs) with 95% confidence intervals (CIs) to express the pooled effects in this meta-analysis.
Results
Eleven studies consisting of 4238 DM patients and 5609 non-DM patients were included in our meta-analysis. For DM patients, successful CTO-PCI was associated with a significantly lower risk of MACEs (RR = 0.67, 95% CI 0.55-0.82, p = 0.0001), all-cause death (RR = 0.46, 95% CI 0.38-0.56, p < 0.00001), and cardiac death (RR = 0.35, 95% CI 0.26-0.48, p < 0.00001) than CTO-medical treatment (MT) alone; however, this does not apply to non-DM patients. Subsequently, the subgroup analysis also obtained consistent conclusions. In addition, our study also revealed that non-DM patients may suffer less risk from MACEs (RR = 1.26, 95% CI 1.02-1.56, p = 0.03) than DM patients after successful CTO-PCI, especially in the subgroup with a follow-up period of less than 3 years (RR = 1.43, 95% CI 1.22-1.67, p < 0.0001).
Conclusions
Compared with CTO-MT alone, successful CTO-PCI was found to be related to a better long-term prognosis in DM patients but not in non-DM patients. However, compared with non-DM patients, the risk of MACEs may be higher in DM patients after successful CTO-PCI in the drug-eluting stent era, especially during a follow-up period shorter than 3 years.



Cardiovasc Diabetol: 29 Jan 2021; 20:29
Zhu Y, Meng S, Chen M, Liu K, ... Zhu H, Jin Z
Cardiovasc Diabetol: 29 Jan 2021; 20:29 | PMID: 33516214
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Impact:
Abstract

Metabolic syndrome, fatty liver, and artificial intelligence-based epicardial adipose tissue measures predict long-term risk of cardiac events: a prospective study.

Lin A, Wong ND, Razipour A, McElhinney PA, ... Berman DS, Dey D
Background
We sought to evaluate the association of metabolic syndrome (MetS) and computed tomography (CT)-derived cardiometabolic biomarkers (non-alcoholic fatty liver disease [NAFLD] and epicardial adipose tissue [EAT] measures) with long-term risk of major adverse cardiovascular events (MACE) in asymptomatic individuals.
Methods
This was a post-hoc analysis of the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study of participants who underwent baseline coronary artery calcium (CAC) scoring CT and 14-year follow-up for MACE (myocardial infarction, late revascularization, or cardiac death). EAT volume (cm3) and attenuation (Hounsfield units [HU]) were quantified from CT using fully automated deep learning software (< 30 s per case). NAFLD was defined as liver-to-spleen attenuation ratio < 1.0 and/or average liver attenuation < 40 HU.
Results
In the final population of 2068 participants (59% males, 56 ± 9 years), those with MetS (n = 280;13.5%) had a greater prevalence of NAFLD (26.0% vs. 9.9%), higher EAT volume (114.1 cm3 vs. 73.7 cm3), and lower EAT attenuation (-76.9 HU vs. -73.4 HU; all p < 0.001) compared to those without MetS. At 14 ± 3 years, MACE occurred in 223 (10.8%) participants. In multivariable Cox regression, MetS was associated with increased risk of MACE (HR 1.58 [95% CI 1.10-2.27], p = 0.01) independently of CAC score; however, not after adjustment for EAT measures (p = 0.27). In a separate Cox analysis, NAFLD predicted MACE (HR 1.78 [95% CI 1.21-2.61], p = 0.003) independently of MetS, CAC score, and EAT measures. Addition of EAT volume to current risk assessment tools resulted in significant net reclassification improvement for MACE (22% over ASCVD risk score; 17% over ASCVD risk score plus CAC score).
Conclusions
MetS, NAFLD, and artificial intelligence-based EAT measures predict long-term MACE risk in asymptomatic individuals. Imaging biomarkers of cardiometabolic disease have the potential for integration into routine reporting of CAC scoring CT to enhance cardiovascular risk stratification. Trial registration NCT00927693.



Cardiovasc Diabetol: 28 Jan 2021; 20:27
Lin A, Wong ND, Razipour A, McElhinney PA, ... Berman DS, Dey D
Cardiovasc Diabetol: 28 Jan 2021; 20:27 | PMID: 33514365
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Impact:
Abstract

Association of pericardial adipose tissue with left ventricular structure and function: a region-specific effect?

Kim JS, Kim SW, Lee JS, Lee SK, ... Shin C, Kim SH
Background
The independent role of pericardial adipose tissue (PAT) as an ectopic fat associated with cardiovascular disease (CVD) remains controversial. This study aimed to determine whether PAT is associated with left ventricular (LV) structure and function independent of other markers of general obesity.
Methods
We studied 2471 participants (50.9 % women) without known CVD from the Korean Genome Epidemiology Study, who underwent 2D-echocardiography with tissue Doppler imaging (TDI) and computed tomography measurement for PAT.
Results
Study participants with more PAT were more likely to be men and had higher cardiometabolic indices, including blood pressure, glucose, and cholesterol levels (all P < 0.001). Greater pericardial fat levels across quartiles of PAT were associated with increased LV mass index and left atrial volume index (all P < 0.001) and decreased systolic (P = 0.015) and early diastolic (P < 0.001) TDI velocities, except for LV ejection fraction. These associations remained after a multivariable-adjusted model for traditional CV risk factors and persisted even after additional adjustment for general adiposity measures, such as waist circumference and body mass index. PAT was also the only obesity index independently associated with systolic TDI velocity (P < 0.001).
Conclusions
PAT was associated with subclinical LV structural and functional deterioration, and these associations were independent of and stronger than with general and abdominal obesity measures.



Cardiovasc Diabetol: 24 Jan 2021; 20:26
Kim JS, Kim SW, Lee JS, Lee SK, ... Shin C, Kim SH
Cardiovasc Diabetol: 24 Jan 2021; 20:26 | PMID: 33494780
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Impact:
Abstract

Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis.

Yu YW, Zhao XM, Wang YH, Zhou Q, ... Zhai M, Zhang J
Background
Although the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular events have been reported in patients with type 2 diabetes mellitus (T2DM) with or without heart failure (HF), the impact of SGLT2i on cardiac remodelling remains to be established.
Methods
We searched the PubMed, Embase, Cochrane Library and Web of Science databases up to November 16th, 2020, for randomized controlled trials reporting the effects of SGLT2i on parameters of cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level or the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. The effect size was expressed as the mean difference (MD) or standardized mean difference (SMD) and its 95% confidence interval (CI). Subgroup analyses were performed based on the stage A-B or stage C HF population and HF types.
Results
Compared to placebo or other antidiabetic drugs, SGLT2i showed no significant effects on left ventricular mass index, left ventricular end diastolic volume index, left ventricular end systolic volume index, or left atrial volume index. SGLT2i improved left ventricular ejection fraction only in the subgroup of HF patients with reduced ejection fraction (MD 3.16%, 95% CI 0.11 to 6.22, p = 0.04; I2 = 0%), and did not affect the global longitudinal strain in the overall analysis including stage A-B HF patients. SGLT2i showed benefits in the E/e\' ratio (MD - 0.45, 95% CI - 0.88 to - 0.03, p = 0.04; I2 = 0%), plasma NT-proBNP level (SMD - 0.09, 95% CI - 0.16 to - 0.03, p = 0.004; I2 = 0%), and the KCCQ score (SMD 3.12, 95% CI 0.76 to 5.47, p  = 0.01; I2 = 0%) in the overall population.
Conclusion
The use of SGLT2i was associated with significant improvements in cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction.



Cardiovasc Diabetol: 24 Jan 2021; 20:25
Yu YW, Zhao XM, Wang YH, Zhou Q, ... Zhai M, Zhang J
Cardiovasc Diabetol: 24 Jan 2021; 20:25 | PMID: 33494751
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Impact:
Abstract

Sex, age, type of diabetes and incidence of atrial fibrillation in patients with diabetes mellitus: a nationwide analysis.

Bisson A, Bodin A, Fauchier G, Herbert J, ... Lip GYH, Fauchier L
Background
There remain uncertainties regarding diabetes mellitus and the incidence of atrial fibrillation (AF), in relation to type of diabetes, and the interactions with sex and age. We investigated whether diabetes confers higher relative rates of AF in women compared to men, and whether these sex-differences depend on type of diabetes and age.
Methods
All patients aged ≥ 18 seen in French hospitals in 2013 with at least 5 years of follow-up without a history of AF were identified and categorized by their diabetes status. We calculated overall and age-dependent incidence rates, hazard ratios, and women-to-men ratios for incidence of AF in patients with type 1 and type 2 diabetes (compared to no diabetes).
Results
In 2,921,407 patients with no history of AF (55% women), 45,389 had prevalent type 1 diabetes and 345,499 had prevalent type 2 diabetes. The incidence rates (IRs) of AF were higher in type 1 or type 2 diabetic patients than in non-diabetics, and increased with advancing age. Among individuals with diabetes, the absolute rate of AF was higher in men than in women. When comparing individuals with and without diabetes, women had a higher adjusted hazard ratio (HR) of AF than men: adjusted HR 1.32 (95% confidence interval 1.27-1.37) in women vs. 1.12(1.08-1.16) in men for type 1 diabetes, adjusted HR 1.17(1.16-1.19) in women vs. 1.10(1.09-1.12) in men for type 2 diabetes.
Conclusion
Although men have higher absolute rates for incidence of AF, the relative rates of incident AF associated with diabetes are higher in women than in men for both type 1 and type 2 diabetes.



Cardiovasc Diabetol: 21 Jan 2021; 20:24
Bisson A, Bodin A, Fauchier G, Herbert J, ... Lip GYH, Fauchier L
Cardiovasc Diabetol: 21 Jan 2021; 20:24 | PMID: 33482830
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Impact:
Abstract

Impact of insulin resistance on subclinical left ventricular dysfunction in normal weight and overweight/obese japanese subjects in a general community.

Hirose K, Nakanishi K, Daimon M, Sawada N, ... Homma S, Komuro I
Background
Insulin resistance carries increased risk of heart failure, although the pathophysiological mechanisms remain unclear. LV global longitudinal strain (LVGLS) assessed by speckle-tracking echocardiography has emerged as an important tool to detect early LV systolic abnormalities. This study aimed to investigate the association between insulin resistance and subclinical left ventricular (LV) dysfunction in a sample of the general population without overt cardiac disease.
Methods
We investigated 539 participants who voluntarily underwent extensive cardiovascular health check including laboratory test and speckle-tracking echocardiography. Glycemic profiles were categorized into 3 groups according to homeostatic model assessment of insulin resistance (HOMA-IR): absence of insulin resistance (HOMA-IR < 1.5), presence of insulin resistance (HOMA-IR ≥ 1.5) and diabetes mellitus (DM). Multivariable logistic regression models were conducted to evaluate the association between abnormal glucose metabolism and impaired LVGLS (> - 16.65%).
Results
Forty-five (8.3%) participants had DM and 66 (12.2%) had abnormal HOMA-IR. LV mass index and E/e\' ratio did not differ between participants with and without abnormal HOMA-IR, whereas abnormal HOMA-IR group had significantly decreased LVGLS (- 17.6 ± 2.6% vs. - 19.7 ± 3.1%, p < 0.05). The prevalence of impaired LVGLS was higher in abnormal HOMA-IR group compared with normal HOMA-IR group (42.4% vs. 14.0%) and similar to that of DM (48.9%). In multivariable analyses, glycemic abnormalities were significantly associated with impaired LVGLS, independent of traditional cardiovascular risk factors and pertinent laboratory and echocardiographic parameters [adjusted odds ratio (OR) 2.38, p = 0.007 for abnormal HOMA-IR; adjusted OR 3.02, p = 0.003 for DM]. The independent association persisted even after adjustment for waist circumference as a marker of abdominal adiposity. Sub-group analyses stratified by body mass index showed significant association between abnormal HOMA-IR and impaired LVGLS in normal weight individuals (adjusted OR 4.59, p = 0.001), but not in overweight/obese individuals (adjusted OR 1.62, p = 0.300).
Conclusions
In the general population without overt cardiac disease, insulin resistance carries independent risk for subclinical LV dysfunction, especially in normal weight individuals.



Cardiovasc Diabetol: 20 Jan 2021; 20:22
Hirose K, Nakanishi K, Daimon M, Sawada N, ... Homma S, Komuro I
Cardiovasc Diabetol: 20 Jan 2021; 20:22 | PMID: 33478525
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Impact:
Abstract

Ten-year cardiovascular risk in diabetes patients without obstructive coronary artery disease: a retrospective Western Denmark cohort study.

Olesen KKW, Madsen M, Gyldenkerne C, Thrane PG, ... Sørensen HT, Maeng M
Background
Diabetes patients without obstructive coronary artery disease as assessed by coronary angiography have a low risk of myocardial infarction, but their myocardial infarction risk may still be higher than the general population. We examined the 10-year risks of myocardial infarction, ischemic stroke, and death in diabetes patients without obstructive coronary artery disease according to coronary angiography, compared to risks in a matched general population cohort.
Methods
We included all diabetes patients without obstructive coronary artery disease examined by coronary angiography from 2003 to 2016 in Western Denmark. Patients were matched by age and sex with a cohort from the Western Denmark general population without a previous myocardial infarction or coronary revascularization. Outcomes were myocardial infarction, ischemic stroke, and death. Ten-year cumulative incidences were computed. Adjusted hazard ratios (HR) then were computed using stratified Cox regression with the general population as reference.
Results
We identified 5734 diabetes patients without obstructive coronary artery disease and 28,670 matched individuals from the general population. Median follow-up was 7 years. Diabetes patients without obstructive coronary artery disease had an almost similar 10-year risk of myocardial infarction (3.2% vs 2.9%, adjusted HR 0.93, 95% CI 0.72-1.20) compared to the general population, but had an increased risk of ischemic stroke (5.2% vs 2.2%, adjusted HR 1.87, 95% CI 1.47-2.38) and death (29.6% vs 17.8%, adjusted HR 1.24, 95% CI 1.13-1.36).
Conclusions
Patients with diabetes and no obstructive coronary artery disease have a 10-year risk of myocardial infarction that is similar to that found in the general population. However, they still remain at increased risk of ischemic stroke and death.



Cardiovasc Diabetol: 20 Jan 2021; 20:23
Olesen KKW, Madsen M, Gyldenkerne C, Thrane PG, ... Sørensen HT, Maeng M
Cardiovasc Diabetol: 20 Jan 2021; 20:23 | PMID: 33478504
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Impact:
Abstract

Cumulative burden of metabolic syndrome and its components on the risk of atrial fibrillation: a nationwide population-based study.

Ahn HJ, Han KD, Choi EK, Jung JH, ... Oh S, Lip GYH
Background
The metabolic syndrome (MetS) and its components are associated with the development of atrial fibrillation (AF). However, the impact of time-burden of MetS on the risk of AF is unknown. We investigated the effect of the cumulative longitudinal burden of MetS on the development of AF.
Methods
We included 2 885 189 individuals without AF who underwent four annual health examinations during 2009-2013 from the database of the Korean national health insurance service. Metabolic burdens were evaluated in the following three ways: (1) cumulative number of MetS diagnosed at each health examination (0-4 times); (2) cumulative number of each MetS component diagnosed at each health examination (0-4 times per MetS component); and (3) cumulative number of total MetS components diagnosed at each health examination (0 to a maximum of 20). The risk of AF according to the metabolic burden was estimated using Cox proportional-hazards models.
Results
Of all individuals, 62.4%, 14.8%, 8.7%, 6.5%, and 7.6% met the MetS diagnostic criteria 0, 1, 2, 3, and 4 times, respectively. During a mean follow-up of 5.3 years, the risk of AF showed a positive association with the cumulative number of MetS diagnosed over four health examinations: adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of 1, 2, 3, and 4 times compared to 0 times were 1.18 (1.13-1.24), 1.31 (1.25-1.39), 1.46 (1.38-1.55), and 1.72 (1.63-1.82), respectively; P for trend < 0.001. All five components of MetS, when diagnosed repeatedly, were independently associated with an increased risk of AF: adjusted HR (95% CI) from 1.22 (1.15-1.29) for impaired fasting glucose to 1.96 (1.87-2.07) for elevated blood pressure. As metabolic components were accumulated from 0 to 20 counts, the risk of AF also gradually increased up to 3.1-fold (adjusted HR 3.11, 95% CI 2.52-3.83 in those with 20 cumulative components of MetS), however, recovery from MetS was linked to a decreased risk of AF.
Conclusions
Given the positive correlations between the cumulative metabolic burdens and the risk of incident AF, maximal effort to detect and correct metabolic derangements even before MetS development might be important to prevent AF and related cardiovascular diseases.



Cardiovasc Diabetol: 18 Jan 2021; 20:20
Ahn HJ, Han KD, Choi EK, Jung JH, ... Oh S, Lip GYH
Cardiovasc Diabetol: 18 Jan 2021; 20:20 | PMID: 33468142
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Impact:
Abstract

Cost-effectiveness of GLP-1 receptor agonists versus insulin for the treatment of type 2 diabetes: a real-world study and systematic review.

Yang CY, Chen YR, Ou HT, Kuo S
Background
To conduct a real-word-study-based cost-effectiveness analysis of a GLP-1 receptor agonist (GLP-1RA) versus insulin among type 2 diabetes patients requiring intensified injection therapy and a systematic review of cost-effectiveness studies of GLP-1RAs versus insulin.
Methods
Individual-level analyses incorporating real-world effectiveness and cost data were conducted for a cohort of 1022 propensity-score-matched pairs of GLP-1RA and insulin users from Taiwan\'s National Health Insurance Research Database, 2007-2016. Study outcomes included the number needed to treat (NNT) to prevent one case of clinical events, healthcare costs, and cost per case of event prevented. Costs were in 2019 US dollars. Analyses were performed from a third-party payer and healthcare sector perspectives. Structured systematic review procedures were conducted to synthesize updated evidence on the cost-effectiveness of GLP-1RAs versus insulin.
Results
Over a mean follow-up of 2.3 years, the NNT using a GLP-1RA versus insulin to prevent one case of all-cause mortality and hospitalized hypoglycemia was 57 and 30, respectively. Using GLP-1RAs instead of insulin cost US$54,851 and US$29,115 per case of all-cause mortality and hospitalized hypoglycemia prevented, respectively, from the payer perspective, and saved US$19,391 and US$10,293, respectively, from the healthcare sector perspective. Sensitivity analyses showed that the probability of using GLP-1RAs versus insulin being cost-effective for preventing one case of all-cause mortality or hospitalized hypoglycemia ranged from 60 to 100%. The systematic review revealed a cost-effective profile of using GLP-1RAs versus insulin.
Conclusions
Using GLP-1RAs versus insulin for type 2 diabetes patients requiring intensified injection therapy in clinical practice is cost-effective.



Cardiovasc Diabetol: 18 Jan 2021; 20:21
Yang CY, Chen YR, Ou HT, Kuo S
Cardiovasc Diabetol: 18 Jan 2021; 20:21 | PMID: 33468131
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Impact:
Abstract

Reduction in cardiovascular mortality following severe hypoglycemia in individuals with type 2 diabetes: the role of a pragmatic and structured intervention : Structured intervention for community hypoglycemia.

Pearson SM, Whittam B, Kulavarasalingam K, Mitchell-Gears A, James C, Ajjan RA
Background
Mortality in individuals with diabetes with severe hypoglycemia requiring ambulance services intervention is high and it is unclear whether this is modifiable. Our aim was to characterise this high-risk group and assess the impact of nurse-led intervention on mortality.
Methods
In this single centre study, patients with diabetes and hypoglycemia requiring ambulance call out were randomized to nurse led support (intensive arm) or managed using existing pathways (standard arm). A third group agreed to have their data collected longitudinally (observational arm). The primary outcome was all-cause mortality comparing intensive with combined standard and observational arms as well as standard arm alone.
Results
Of 828 individuals identified, 323 agreed to participate with 132 assigned to intensive, 130 to standard and 61 to observational arms. Mean follow up period was 42.6 ± 15.6 months. Mortality in type 1 diabetes (n = 158) was similar across study arms but in type 2 diabetes (n = 160) this was reduced to 33% in the intensive arm compared with 51% in the combined arm (p = 0.025) and 50% in the standard arm (p = 0.06). Cardiovascular deaths, the leading cause of mortality, was lower in the intensive arm compared with combined and standard study arms (p < 0.01).
Conclusions
Medium-term mortality following severe hypoglycemia requiring the assistance of emergency services is high in those with type 2 diabetes. In individuals with type 2 diabetes, nurse-led individualized intervention reduces cardiovascular mortality compared with standard care. Large-scale multicentre studies are warranted to further investigate this approach. Trial registration The trial was retrospectively registered on http://www.clinicaltrials.gov with reference NCT04422145.



Cardiovasc Diabetol: 11 Jan 2021; 20:18
Pearson SM, Whittam B, Kulavarasalingam K, Mitchell-Gears A, James C, Ajjan RA
Cardiovasc Diabetol: 11 Jan 2021; 20:18 | PMID: 33435992
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Impact:
Abstract

Triglyceride-glucose index is associated with the risk of myocardial infarction: an 11-year prospective study in the Kailuan cohort.

Tian X, Zuo Y, Chen S, Liu Q, ... Wu S, Wang A
Background
The triglyceride-glucose (TyG) index, which is a simple surrogate marker of insulin resistance, has been suggested as a contributor of cardiovascular disease. However, evidence on the effect of long-term elevation of the TyG index exposure on myocardial infarction (MI) is limited. The current study aimed to evaluate the association of baseline and long-term elevation of the TyG index exposure with the risk of MI.
Methods
A total of 98,849 participants without MI at baseline (2006) were enrolled from the Kailuan study. The baseline TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. The long-term TyG index was characterized in two ways as follows. The updated mean TyG index was calculated as the mean of TyG index at all previous visits before MI occurred or the end of follow-up; alternatively, the TyG index was calculated as the number of visits with a high TyG index in 2006, 2008, and 2010, ranging from 0 (no exposure) to 3 (had high TyG index at all three study visits). Hazard ratio (HR) and 95% confidence interval (CI) was estimated using multivariable Cox proportion hazard models.
Results
During a median follow-up of 11.03 years, 1555 incident MI occurred. In the multivariable-adjusted model, the risk of MI increased with quartiles of the baseline and updated mean TyG index, the HR in quartile 4 versus quartile 1 was 2.08 (95% CI,1.77-2.45) and 1.58 (1.18-2.12), respectively. Individuals with a high TyG index at all three visits had a 2.04-fold higher risk (95% CI, 1.63-2.56) of MI compared with no exposure. Subgroup analyses showed that the associations were more pronounced in women than in men (Pinteraction = 0.0411).
Conclusions
Elevated levels of the baseline and long-term TyG index are associated with an increased risk of MI. This finding indicates that the TyG index might be useful in identifying people at high risk of developing MI.



Cardiovasc Diabetol: 11 Jan 2021; 20:19
Tian X, Zuo Y, Chen S, Liu Q, ... Wu S, Wang A
Cardiovasc Diabetol: 11 Jan 2021; 20:19 | PMID: 33435964
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Impact:
Abstract

Real-world outcomes of different treatment strategies in patients with diabetes and three-vessel coronary disease: a mean follow-up 6.3 years study from China.

Zhao X, Xu L, Jiang L, Tian J, ... Song L, Yuan J
Background
Patients with diabetes and triple-vessel disease (TVD) are associated with a high risk of events. The choice of treatment strategies remains a subject of discussion. In the real-world, we aim to compare the outcomes of medical therapy (MT), coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI) treatment strategies in patients with diabetes and TVD.
Methods
A total of 3117 consecutive patients with diabetes and TVD were enrolled. The primary endpoint was all-cause death and the secondary endpoint was major adverse cardiac and cerebrovascular events (MACCE, composite of all-cause death, myocardial infarction, or stroke).
Results
During the mean follow-up of 6.3 ± 2.6 years, 573 (18.4%) deaths and 1094 (35.1%) MACCE occurred. Multivariate analysis showed that PCI (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.32-0.51) and CABG (HR 0.33, 95% CI 0.26-0.44) were associated with a lower risk of death compared with MT, with no difference between the PCI and CABG groups. When MACCE was the endpoint, PCI (HR 0.71, 95% CI 0.60-0.84) and CABG (HR 0.48, 95% CI 0.39-0.57) had a lower risk than MT. CABG was associated with a significantly lower risk of MACCE compared with PCI (HR 0.67, 95% CI 0.55-0.81), which was mainly attributed a lower risk in myocardial infarction, but a higher risk of stroke.
Conclusions
In this big real-world data and intermediate-term follow-up study, for patients with diabetes and TVD, PCI and CABG were associated with a lower risk of death and MACCE more than MT. The results suggest the importance of appropriate revascularization for diabetic patients with TVD. However, CABG was not associated with a lower risk of death, but with a lower risk of MACCE, compared with PCI. In the future, we perhaps should strengthen comprehensive treatment in addition to PCI or CABG.



Cardiovasc Diabetol: 10 Jan 2021; 20:16
Zhao X, Xu L, Jiang L, Tian J, ... Song L, Yuan J
Cardiovasc Diabetol: 10 Jan 2021; 20:16 | PMID: 33430864
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Impact:
Abstract

Sodium-glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes.

Giugliano D, Longo M, Scappaticcio L, Caruso P, Esposito K
Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.



Cardiovasc Diabetol: 10 Jan 2021; 20:17
Giugliano D, Longo M, Scappaticcio L, Caruso P, Esposito K
Cardiovasc Diabetol: 10 Jan 2021; 20:17 | PMID: 33430860
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Impact:
Abstract

Effects of liraglutide on diastolic function parameters in patients with type 2 diabetes and coronary artery disease: a randomized crossover study.

Kumarathurai P, Sajadieh A, Anholm C, Kristiansen OP, Haugaard SB, Nielsen OW
Background
Diastolic dysfunction is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and is associated with overweight, glucose dysregulation and coronary artery disease (CAD). The GLP-1 receptor agonist, liraglutide, has shown to induce weight loss and improve metabolic factors, thus modulating factors associated with diastolic dysfunction. We have previously reported the effects of liraglutide on systolic function, and in this current study we explore the effects of liraglutide on diastolic function parameters in patients with stable CAD, preserved left ventricular ejection fraction (LVEF), and newly diagnosed T2DM.
Methods
Thirty subjects were randomized to liraglutide or placebo intervention for 12 + 12-weeks in this double-blind cross-over study. 2D-echocardiography using tissue velocity imaging was used for assessment of diastolic function parameters. Early diastolic filling velocity (E), late atrial filling velocity (A), E-wave deceleration time (EDT) and E/A ratio was assessed from the pulse wave (PW)-Doppler velocity recording of the mitral inflow. Peak early diastolic annular velocities (e\') was measured from color tissue doppler images.
Results
Liraglutide, when compared to placebo, induced a significant reduction in average e\' and lateral e\' velocities (- 0.57 cm/s [- 1.05 to - 0.08] and -0.74 cm/s [-1.32 to -0.15], respectively). Adjusted for the concomitant increase in HR (+ 6.16 bpm [0.79 to 11.54], the changes were not significant. No significant changes in other diastolic function parameters were observed.
Conclusions
Liraglutide therapy did not improve any diastolic function parameters in subjects with T2DM, CAD, and preserved LVEF. Instead, a deterioration in e\' was observed, which was associated to an increase in heart rate induced by liraglutide therapy. Trial registration Clinical Trial Registration: http://www.clinicaltrials.gov (unique identifier: NCT01595789) (first submitted May 8, 2012).



Cardiovasc Diabetol: 06 Jan 2021; 20:12
Kumarathurai P, Sajadieh A, Anholm C, Kristiansen OP, Haugaard SB, Nielsen OW
Cardiovasc Diabetol: 06 Jan 2021; 20:12 | PMID: 33413428
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Impact:
Abstract

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF.

Bode D, Semmler L, Wakula P, Hegemann N, ... Heinzel FR, Hohendanner F
Background
Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.
Methods
17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student\'s t-test, as applicable.
Results
Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition.
Conclusion
The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.



Cardiovasc Diabetol: 06 Jan 2021; 20:7
Bode D, Semmler L, Wakula P, Hegemann N, ... Heinzel FR, Hohendanner F
Cardiovasc Diabetol: 06 Jan 2021; 20:7 | PMID: 33413413
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Impact:
Abstract

The additive effects of kidney dysfunction on left ventricular function and strain in type 2 diabetes mellitus patients verified by cardiac magnetic resonance imaging.

Zhang Y, Wang J, Ren Y, Yan WF, ... Li Y, Yang ZG
Background
Patients with type 2 diabetes mellitus (T2DM) are susceptible to coexisted with chronic kidney disease (CKD), which may increase cardiovascular mortality in these patients. The present study aimed to verify whether CKD aggravates the deterioration of left ventricular (LV) myocardial strain in T2DM patients and to explore the risk factors associated with LV strain.
Materials and methods
In total, 105 T2DM patients and 52 healthy individuals were included and underwent cardiac magnetic resonance examination. Patients were divided into the following two groups: T2DM with CKD (n = 33) and T2DM without CKD (n = 72). The baseline clinical and biochemical indices were obtained from hospital records before the cardiac magnetic resonance scan. Cine sequences, including long-axis views (2-chamber and 4-chamber) and short-axis views, were acquired. LV function and global strain parameters were measured based on cine sequences and compared among three groups. Pearson\'s analysis was performed to investigate the correlation between LV strain parameters and clinical indices. Multiple linear regression analysis was used to identify the independent indicators of LV strain.
Results
Compared with normal controls, T2DM patients without CKD had a significantly decreased magnitude of peak strain (PS; radial), peak systolic strain rate (radial), and peak diastolic strain rate (radial and circumferential) (all P < 0.05). Furthermore, T2DM patients with CKD displayed markedly lower magnitudes of PS (radial, circumferential, and longitudinal) and peak diastolic strain rate (circumferential and longitudinal) than both normal controls and T2DM patients without CKD (all P < 0.05). The eGFR was positively associated with the magnitude of PS (R = radial, 0.392; circumferential, 0.436; longitudinal, 0.556), while uric acid was negatively associated with the magnitude of PS (R = radial, - 0.361; circumferential, - 0.391; longitudinal, - 0.460) (all P < 0.001). Multivariable linear regression indicated that the magnitude of PS was independently associated with eGFR (β = radial, 0.314; circumferential, 0.292; longitudinal, 0.500) and uric acid (β = radial, - 0.239; circumferential, - 0.211; longitudinal, - 0.238) (all P < 0.05).
Conclusions
Kidney dysfunction may aggravate the deterioration of LV strain in T2DM patients. LV strain is positively associated with the estimated glomerular filtration rate and negatively associated with uric acid, which may be independent risk factors for predicting reduction of LV strain.



Cardiovasc Diabetol: 06 Jan 2021; 20:11
Zhang Y, Wang J, Ren Y, Yan WF, ... Li Y, Yang ZG
Cardiovasc Diabetol: 06 Jan 2021; 20:11 | PMID: 33413395
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Impact:
Abstract

Comprehensive elaboration of glycemic variability in diabetic macrovascular and microvascular complications.

Sun B, Luo Z, Zhou J
Diabetes mellitus is the major risk factor for the development of macrovascular and microvascular complications. It is increasingly recognized that glycemic variability (GV), referring to oscillations in blood glucose levels and representing either short-term or long-term GV, is involved in the pathogenesis of diabetic complications and has emerged as a possible independent risk factor for them. In this review, we summarize the metrics and measurement of GV in clinical practice, as well as comprehensively elaborate the role and related mechanisms of GV in diabetic macrovascular and microvascular complications, aiming to provide the mechanism-based therapeutic strategies for clinicians to manage diabetes mellitus.



Cardiovasc Diabetol: 06 Jan 2021; 20:9
Sun B, Luo Z, Zhou J
Cardiovasc Diabetol: 06 Jan 2021; 20:9 | PMID: 33413392
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Impact:
Abstract

Relationship between insulin resistance, coronary plaque, and clinical outcomes in patients with acute coronary syndromes: an analysis from the PROSPECT study.

Farhan S, Redfors B, Maehara A, McAndrew T, ... Mintz GS, Stone GW
Background
We investigated the association of insulin resistance (IR) with coronary plaque morphology and the risk of cardiovascular events in patients enrolled in the Providing Regional Observations to Study Predictors of Events in Coronary Tree (PROSPECT) study.
Methods
Patients with acute coronary syndromes (ACS) were divided based on DM status. Non-DM patients were further stratified according to homeostasis-model-assessment IR (HOMA-IR) index as insulin sensitive (IS; HOMA-IR ≤ 2), likely-IR (LIR; 2 < HOMA-IR < 5), or diabetic-IR (DIR; HOMA-IR ≥ 5). Coronary plaque characteristics were investigated by intravascular ultrasound. The primary endpoint was major adverse cardiac events (MACE); a composite of cardiac death, cardiac arrest, myocardial infarction, and rehospitalization for unstable/progressive angina.
Results
Among non-diabetic patients, 109 patients (21.5%) were categorized as LIR, and 65 patients (12.8%) as DIR. Patients with DIR or DM had significantly higher rates of echolucent plaque compared with LIR and IS. In addition, DIR and DM were independently associated with increased risk of MACE compared with IS (adjusted hazard ratio [aHR] 2.29, 95% confidence interval [CI] 1.22-4.29, p = 0.01 and aHR 2.12, 95% CI 1.19-3.75, p = 0.009, respectively).
Conclusions
IR is common among patients with ACS. DM and advanced but not early stages of IR are independently associated with increased risk of adverse cardiovascular events.
Trial registration:
ClinicalTrials.gov Identifier: NCT00180466.



Cardiovasc Diabetol: 06 Jan 2021; 20:10
Farhan S, Redfors B, Maehara A, McAndrew T, ... Mintz GS, Stone GW
Cardiovasc Diabetol: 06 Jan 2021; 20:10 | PMID: 33413366
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Impact:
Abstract

Prognostic value of non-alcoholic fatty liver disease for predicting cardiovascular events in patients with diabetes mellitus with suspected coronary artery disease: a prospective cohort study.

Ichikawa K, Miyoshi T, Osawa K, Miki T, ... Morita H, Ito H
Background
Risk stratification of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) has not been established. Coronary artery calcium score (CACS) and non-alcoholic fatty liver disease (NAFLD) are independently associated with cardiovascular events in T2DM patients. This study examined the incremental prognostic value of NAFLD assessed by non-enhanced computed tomography (CT) in addition to CACS and Framingham risk score (FRS) for cardiovascular events in T2DM patients.
Methods
This prospective pilot study included 529 T2DM outpatients with no history of cardiovascular disease who underwent CACS measurement because of suspected coronary artery disease. NAFLD was defined on CT images as a liver:spleen attenuation ratio < 1.0. Cardiovascular events were defined as cardiovascular death, nonfatal myocardial infarction, late coronary revascularization, nonfatal stroke, or hospitalization for heart failure.
Results
Among 529 patients (61% men, mean age 65 years), NAFLD was identified in 143 (27%). Forty-four cardiovascular events were documented during a median follow-up of 4.4 years. In multivariate Cox regression analysis, NAFLD, CACS, and FRS were associated with cardiovascular events (hazard ratios and 95% confidence intervals 5.43, 2.82-10.44, p < 0.001; 1.56, 1.32-1.86, p < 0.001; 1.23, 1.08-1.39, p = 0.001, respectively). The global χ2 score for predicting cardiovascular events increased significantly from 27.0 to 49.7 by adding NAFLD to CACS and FRS (p < 0.001). The addition of NAFLD to a model including CACS and FRS significantly increased the C-statistic from 0.71 to 0.80 (p = 0.005). The net reclassification achieved by adding CACS and FRS was 0.551 (p < 0.001).
Conclusions
NAFLD assessed by CT, in addition to CACS and FRS, could be useful for identifying T2DM patients at higher risk of cardiovascular events.



Cardiovasc Diabetol: 06 Jan 2021; 20:8
Ichikawa K, Miyoshi T, Osawa K, Miki T, ... Morita H, Ito H
Cardiovasc Diabetol: 06 Jan 2021; 20:8 | PMID: 33413363
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Impact:
Abstract

Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study.

Rau M, Thiele K, Hartmann NK, Schuh A, ... Marx N, Lehrke M
Background
In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function.
Methods
In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment.
Results
Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/e\') which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003).
Conclusions
Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu).



Cardiovasc Diabetol: 06 Jan 2021; 20:6
Rau M, Thiele K, Hartmann NK, Schuh A, ... Marx N, Lehrke M
Cardiovasc Diabetol: 06 Jan 2021; 20:6 | PMID: 33413355
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Impact:
Abstract

Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis.

Yamada T, Wakabayashi M, Bhalla A, Chopra N, ... Wakui H, Tamura K
Background
Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients.
Methods
We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.
Results
Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]).
Conclusions
In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.



Cardiovasc Diabetol: 06 Jan 2021; 20:14
Yamada T, Wakabayashi M, Bhalla A, Chopra N, ... Wakui H, Tamura K
Cardiovasc Diabetol: 06 Jan 2021; 20:14 | PMID: 33413348
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Impact:
Abstract

Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study.

Nicholls SJ, Schwartz GG, Buhr KA, Ginsberg HN, ... Ray KK, BETonMACE Investigators
Background
Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known.
Methods
The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied.
Results
Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38-0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27-0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53-0.98], P = 0.04).
Conclusion
Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.



Cardiovasc Diabetol: 06 Jan 2021; 20:13
Nicholls SJ, Schwartz GG, Buhr KA, Ginsberg HN, ... Ray KK, BETonMACE Investigators
Cardiovasc Diabetol: 06 Jan 2021; 20:13 | PMID: 33413345
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Impact:
Abstract

Associations between continuous glucose monitoring-derived metrics and arterial stiffness in Japanese patients with type 2 diabetes.

Wakasugi S, Mita T, Katakami N, Okada Y, ... Shimomura I, Watada H
Background
Previous studies have suggested that high mean glucose levels and glycemic abnormalities such as glucose fluctuation and hypoglycemia accelerate the progression of atherosclerosis in patients with type 2 diabetes. Although continuous glucose monitoring (CGM) that could evaluate such glycemic abnormalities has been rapidly adopted, the associations between CGM-derived metrics and arterial stiffness are not entirely clear.
Methods
This exploratory cross-sectional study used baseline data from an ongoing prospective, multicenter, observational study with 5 years of follow-up. Study participants included 445 outpatients with type 2 diabetes and no history of apparent cardiovascular disease who underwent CGM and brachial-ankle pulse wave velocity (baPWV) measurement at baseline. Associations between CGM-derived metrics and baPWV were analyzed using multivariate regression models.
Results
In a linear regression model, all CGM-derived metrics were significantly associated with baPWV, but HbA1c was not. Some CGM-derived metrics related to intra-day glucose variability, hyperglycemia, and hypoglycemia remained significantly associated with baPWV after adjusting for possible atherosclerotic risk factors, including HbA1c. Based on baPWV ≥ 1800 cm/s as indicative of high arterial stiffness, multivariate logistic regression found that some CGM-derived metrics related to intra-day glucose variability and hyperglycemia are significantly associated with high arterial stiffness even after adjusting for possible atherosclerotic risk factors, including HbA1c.
Conclusions
Multiple CGM-derived metrics are significantly associated with baPWV and high arterial stiffness in patients with type 2 diabetes who have no history of apparent cardiovascular disease. These metrics might be useful for identifying patients at high risk of developing cardiovascular disease.



Cardiovasc Diabetol: 06 Jan 2021; 20:15
Wakasugi S, Mita T, Katakami N, Okada Y, ... Shimomura I, Watada H
Cardiovasc Diabetol: 06 Jan 2021; 20:15 | PMID: 33413339
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Impact:
Abstract

Association between the Mediterranean lifestyle, metabolic syndrome and mortality: a whole-country cohort in Spain.

Sotos-Prieto M, Ortolá R, Ruiz-Canela M, Garcia-Esquinas E, ... Martínez-González MÁ, Rodriguez-Artalejo F
Background
Evidence is limited about the joint health effects of the Mediterranean lifestyle on cardiometabolic health and mortality. The aim of this study was to evaluate the association of the Mediterranean lifestyle with the frequency of the metabolic syndrome (MS) and the risk of all-cause and cardiovascular mortality in Spain.
Methods
Data were taken from ENRICA study, a prospective cohort of 11,090 individuals aged 18+ years, representative of the population of Spain, who were free of cardiovascular disease (CVD) and diabetes at 2008-2010 and were followed-up to 2017. The Mediterranean lifestyle was assessed at baseline with the 27-item MEDLIFE index (with higher score representing better adherence).
Results
Compared to participants in the lowest quartile of MEDLIFE, those in the highest quartile had a multivariable-adjusted odds ratio 0.73 (95% confidence interval (CI) 0.5, 0.93) for MS, 0.63. (0.51, 0.80) for abdominal obesity, and 0.76 (0.63, 0.90) for low HDL-cholesterol. Similarly, a higher MELDIFE score was associated with lower HOMA-IR and highly-sensitivity C-reactive protein (P-trend < 0.001). During a mean follow-up of 8.7 years, 330 total deaths (74 CVD deaths) were ascertained. When comparing those in highest vs. lowest quartile of MEDLIFE, the multivariable-adjusted hazard ratio (95% CI) was 0.58 (0.37, 0.90) for total mortality and 0.33 (0.11, 1.02) for cardiovascular mortality.
Conclusions
The Mediterranean lifestyle was associated with lower frequency of MS and reduced all-cause mortality in Spain. Future studies should determine if this also applies to other Mediterranean countries, and also improve cardiovascular health outside the Mediterranean basin.



Cardiovasc Diabetol: 04 Jan 2021; 20:5
Sotos-Prieto M, Ortolá R, Ruiz-Canela M, Garcia-Esquinas E, ... Martínez-González MÁ, Rodriguez-Artalejo F
Cardiovasc Diabetol: 04 Jan 2021; 20:5 | PMID: 33402187
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Impact:
Abstract

Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial.

Tuttolomondo A, Cirrincione A, Casuccio A, Del Cuore A, ... Scaglione S, Pinto A
Background
Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage.
Aims
We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes.
Methods
Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose- lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels.
Results
At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy.
Conclusions
Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers.



Cardiovasc Diabetol: 03 Jan 2021; 20:1
Tuttolomondo A, Cirrincione A, Casuccio A, Del Cuore A, ... Scaglione S, Pinto A
Cardiovasc Diabetol: 03 Jan 2021; 20:1 | PMID: 33397395
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Impact:
Abstract

Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.

Katakami N, Mita T, Yoshii H, Shiraiwa T, ... Shimomura I, UTOPIA study investigators
Background
Tofogliflozin, an SGLT2 inhibitor, is associated with favorable metabolic effects, including improved glycemic control and serum lipid profile and decreased body weight, visceral adipose tissue, and blood pressure (BP). This study evaluated the effects of tofogliflozin on the brachial-ankle pulse wave velocity (baPWV) in patients with type 2 diabetes (T2DM) without a history of apparent cardiovascular disease.
Methods
The using tofogliflozin for possible better intervention against atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. As one of the prespecified secondary outcomes, changes in baPWV over 104 weeks were evaluated in 154 individuals (80 in the tofogliflozin group and 74 in the conventional treatment group) who completed baPWV measurement at baseline.
Results
In a mixed-effects model, the progression in the right, left, and mean baPWV over 104 weeks was significantly attenuated with tofogliflozin compared to that with conventional treatment (- 109.3 [- 184.3, - 34.3] (mean change [95% CI] cm/s, p = 0.005; - 98.3 [- 172.6, - 24.1] cm/s, p = 0.010; - 104.7 [- 177.0, - 32.4] cm/s, p = 0.005, respectively). Similar findings were obtained even after adjusting the mixed-effects models for traditional cardiovascular risk factors, including body mass index (BMI), glycated hemoglobin (HbA1c), total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, systolic blood pressure (SBP), hypertension, smoking, and/or administration of drugs, including hypoglycemic agents, antihypertensive agents, statins, and anti-platelets, at baseline. The findings of the analysis of covariance (ANCOVA) models, which included the treatment group, baseline baPWV, and traditional cardiovascular risk factors, resembled those generated by the mixed-effects models.
Conclusions
Tofogliflozin significantly inhibited the increased baPWV in patients with T2DM without a history of apparent cardiovascular disease, suggesting that tofogliflozin suppressed the progression of arterial stiffness.
Trial registration:
UMIN000017607. Registered 18 May 2015. ( https://www.umin.ac.jp/icdr/index.html ).



Cardiovasc Diabetol: 03 Jan 2021; 20:4
Katakami N, Mita T, Yoshii H, Shiraiwa T, ... Shimomura I, UTOPIA study investigators
Cardiovasc Diabetol: 03 Jan 2021; 20:4 | PMID: 33397376
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Impact:
Abstract

Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy.

Wang L, Cai Y, Jian L, Cheung CW, Zhang L, Xia Z
The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium-glucose co-transporter 2 inhibitor) in treating DCM.



Cardiovasc Diabetol: 03 Jan 2021; 20:2
Wang L, Cai Y, Jian L, Cheung CW, Zhang L, Xia Z
Cardiovasc Diabetol: 03 Jan 2021; 20:2 | PMID: 33397369
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Impact:
Abstract

History of lower-limb complications and risk of cancer death in people with type 2 diabetes.

Mohammedi K, Harrap S, Mancia G, Marre M, ... Chalmers J, Woodward M
Background
Individuals with diabetes and lower-limb complications are at high risk for cardiovascular and all-cause mortality, but uncertainties remain in terms of cancer-related death in this population. We investigated this relationship in a large cohort of people with type 2 diabetes.
Methods
We used data from the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) study. The primary outcome was adjudicated cancer death; secondary outcomes were overall and site-specific incident cancers, determined according to the International Classification of Diseases Code (ICD-10). We compared outcomes in individuals with (versus without) a baseline history of lower-limb complications (peripheral artery disease (PAD) or sensory peripheral neuropathy) using Cox regression models.
Results
Among 11,140 participants (women 42%, mean age 66 years), lower-limb complications were reported at baseline in 4293 (38%) individuals: 2439 (22%) with PAD and 2973 (27%) with peripheral neuropathy. Cancer death occurred in 316 (2.8%) participants during a median of 5.0 (25th-75th percentile, 4.7-5.1) years of follow-up corresponding to 53,550 person-years and an incidence rate of 5.9 (95% CI 5.3-6.6) per 1000 person-years. The risk of cancer death was higher in individuals with (versus without) lower-limb complication [hazard ratio 1.53 (95% CI, 1.21-1.94), p = 0.0004], PAD [1.32 (1.02-1.70), p = 0.03] or neuropathy (1.41 (1.11-1.79), p = 0.004], adjusting for potential confounders and study allocations. PAD, but not neuropathy, was associated with excess risk of incident cancers.
Conclusions
PAD and peripheral neuropathy were independently associated with increased 5-year risk of cancer death in individuals with type 2 diabetes. PAD was also associated with increased risk of incident cancers. Our findings provide new evidence on the non-cardiovascular prognostic burden of lower-limb complications in people with type 2 diabetes.



Cardiovasc Diabetol: 03 Jan 2021; 20:3
Mohammedi K, Harrap S, Mancia G, Marre M, ... Chalmers J, Woodward M
Cardiovasc Diabetol: 03 Jan 2021; 20:3 | PMID: 33397352
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