Prevalence of diabetic cardiomyopathy in patients with type 2 diabetes in a large academic medical center.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is characterized by asymptomatic stage B heart failure (SBHF) caused by diabetes-related metabolic alterations. DbCM is associated with an increased risk of progression to overt heart failure (HF). The prevalence of DbCM in patients with type 2 diabetes (T2D) is not well established. This study aims to determine prevalence of DbCM in adult T2D patients in real-world clinical practice. METHODS: Retrospective multi-step review of electronic medical records of patients with the diagnosis of T2D who had echocardiogram at UC San Diego Medical Center (UCSD) within 2010-2019 was conducted to identify T2D patients with SBHF. We defined "pure" DbCM when SBHF is associated solely with T2D and "mixed" SBHF when other medical conditions can contribute to SBHF. "Pure" DbCM was diagnosed in T2D patients with echocardiographic demonstration of SBHF defined as left atrial (LA) enlargement (LAE), as evidenced by LA volume index ≥ 34 mL/m2, in the presence of left ventricular ejection fraction (LVEF) ≥ 45%, while excluding overt HF and comorbidities that can contribute to SBHF. RESULTS: Of 778,314 UCSD patients in 2010-2019, 45,600 (5.9%) had T2D diagnosis. In this group, 15,182 T2D patients (33.3%) had echocardiogram and, among them, 13,680 (90.1%) had LVEF ≥ 45%. Out of 13,680 patients, 4,790 patients had LAE. Of them, 1,070 patients were excluded due to incomplete data and/or a lack of confirmed T2D according to the American Diabetes Association recommendations. Thus, 3,720 T2D patients with LVEF ≥ 45% and LAE were identified, regardless of HF symptoms. In this group, 1,604 patients (43.1%) had overt HF and were excluded. Thus, 2,116 T2D patients (56.9% of T2D patients with LVEF ≥ 45% and LAE) with asymptomatic SBHF were identified. Out of them, 1,773 patients (83.8%) were diagnosed with "mixed" SBHF due to comorbidities such as hypertension (58%), coronary artery disease (36%), and valvular heart disease (17%). Finally, 343 patients met the diagnostic criteria of "pure" DbCM, which represents 16.2% of T2D patients with SBHF, i.e., at least 2.9% of the entire T2D population in this study. CONCLUSIONS: Our findings provide insights into prevalence of DbCM in real-world clinical practice and indicate that DbCM affects a significant portion of T2D patients.

Prevalence and clinical characteristics of diabetic cardiomyopathy in patients with acute heart failure.

BACKGROUND AND AIMS: Diabetic cardiomyopathy refers to cases of diabetes mellitus (DM) complicated by cardiac dysfunction in the absence of cardiovascular disease and hypertension. Its epidemiology remains unclear due to the high rate of coexistence between DM and hypertension. Therefore, this study aimed to examine the prevalence and clinical characteristics of diabetic cardiomyopathy among patients with acute heart failure (HF). METHODS AND RESULTS: This multicenter, retrospective study included 17,614 consecutive patients with acute HF. DM-related HF was defined as HF complicating DM without known manifestations of coronary artery disease, significant valvular heart disease, or congenital heart disease, while diabetic cardiomyopathy was defined as DM-related HF without hypertension. Univariable and multivariable logistic regression analyses were performed to identify factors associated with in-hospital mortality. Diabetic cardiomyopathy prevalence was 1.6 % in the entire cohort, 5.2 % in patients with acute HF complicating DM, and 10 % in patients with DM-related HF. Clinical characteristics, including the presence of comorbidities, laboratory data on admission, and factors associated with in-hospital mortality, significantly differed between the diabetic cardiomyopathy group and the DM-related HF with hypertension group. The in-hospital mortality rate was significantly higher in patients with diabetic cardiomyopathy than in patients with DM-related HF with hypertension (7.7 % vs. 2.8 %, respectively; P < 0.001). CONCLUSION: The prevalence of diabetic cardiomyopathy was 1.6 % in patients with acute HF, and patients with diabetic cardiomyopathy were at high risk for in-hospital mortality. The clinical characteristics of patients with diabetic cardiomyopathy were significantly different than those of patients with DM-related HF with hypertension.

Effects of a low carbohydrate diet on heart failure symptoms and quality of life in patients with diabetic cardiomyopathy: A randomised controlled trial pilot study.

BACKGROUND AND AIMS: Heart failure, insulin resistance and/or type 2 diabetes mellitus coexist in the syndrome that is diabetic cardiomyopathy. Patients with diabetic cardiomyopathy experience high symptom burden and poor quality of life. We tested the hypothesis that a low carbohydrate diet improves heart failure symptoms and quality of life in patients with diabetic cardiomyopathy. METHODS AND RESULTS: We conducted a 16-week randomised controlled pilot trial comparing the effects of a low carbohydrate diet (LC) to usual care (UC) in 17 adult patients with diabetic cardiomyopathy. New York Heart Association classification, weight, thirst distress and quality of life scores as well as blood pressure and biochemical data were assessed at baseline and at 16 weeks. Thirteen (n = 8 LC; n = 5 UC) patients completed the trial. The low carbohydrate diet induced significant weight loss in completers (p = 0.004). There was a large between-group difference in systolic blood pressure at the end of the study (Hedges's g 0.99[-014,2.08]). There were no significant differences in thirst or quality of life between groups. CONCLUSION: This is the first clinical trial utilising the low carbohydrate dietary approach in patients with diabetic cardiomyopathy in an outpatient setting. A low carbohydrate diet can lead to significant weight loss in patients with diabetic cardiomyopathy. Future clinical trials with larger samples and that focus on fluid and sodium requirements of patients with diabetic cardiomyopathy who engage in a low carbohydrate diet are warranted. CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ANZCTR): ACTRN12620001278921. DATE OF REGISTRATION: 26th November 2020.

[Impact of smoking on the presence of diabetic cardiomyopathy]. / Impact du tabagisme sur la présence de la cardiomyopathie diabétique.

INTRODUCTION: Type 2 diabetes is associated with an increased risk of coronary disease and is the leading cause of morbidity and mortality in this population. The main objective of our work is to study the correlation of left atrial volume index with coronary disease in type 2 diabetics. MATERIAL AND METHODS: Cross-sectional, analytical, single-center study with prospective recruitment of 330 type 2 diabetic patients carried out at the Constantine Regional Military University Hospital over a period of 03 years (2016-2018) among which 18.8% (62 patients) are smokers. Early cardiac involvement represented by diastolic dysfunction was assessed by two-dimensional transthoracic echocardiography. Data were analyzed using Epi info 7.2.1.0 software to study the impact of smoking on the presence of left ventricular diastolic dysfunction. RESULTS: The average age of our cohort is 52.7 ± 8.4 years, an average of 7.1 ± 1.3% of glycated hemoglobin, an average of 5.3 ± 4.3 years of diabetes duration, a sex ratio to 1.01. 34.8% of patients had left atrial volume index ≥ 34 ml/m2. The prevalence of coronary disease is 27.0%. In multivariate analysis; left atrial volume index is significantly correlated with coronary stenosis (OR = 1.75, 95% CI [1.60 - 2.05], p = 0.02). CONCLUSION: The prevalence of cardiomyopathy is high in type 2 diabetes and smoking is significantly correlated with the presence of this diabetic cardiomyopathy.

Echocardiographic phenotypes of Chinese patients with type 2 diabetes may indicate early diabetic myocardial disease.

AIM: Type 2 diabetes may impair cardiac structure and function at very early stage, other factors, for example, obesity and hypertension, can induce aforementioned abnormalities individually. This study aimed to explore precise prevention and treatment of diabetic cardiomyopathy (DCM) by using cluster analysis of echocardiographic variables. METHODS AND RESULTS: A total of 66 536 inpatients with diabetes from 2013 to 2018 were investigated, and 7112 patients were available for analysis after nadir. The cluster analysis was performed on echocardiographic variables to assess the clinical profiles and risk factors of clusters. Two clusters were identified. Cluster 1 with 3576 patients (50.3%, including 62.5% female) had hypertension in 62.4%, while the lower rate of obesity (13.7%). Ultrasound findings showed that 79.9% of them had left ventricular diastolic dysfunction (LVDD), the most characteristic change in the early stages of DCM. Systolic blood pressure (SBP), uric acid and antithrombin III were independent risk factors for LVDD (P < 0.0001); 64.0% of the 3536 patients in the second group were male, with a high prevalence of obesity (30.1%) and a higher prevalence of hypertension (79.5%), In particular, decreased systolic function and a high rate of LV hypertrophy (46.8%) represented the progressive phase of DCM (P < 0.0001). SBP, diastolic blood pressure, BMI and creatinine were independent correlates of LV mass index (P < 0.05). CONCLUSION: The cluster analysis of echocardiographic variables may improve the identification of groups of patients with similar risks and different disease courses and will facilitate the achievement of targeted early prevention and treatment of DCM.

Identification of Crucial Genes and Key Functions in Type 2 Diabetic Hearts by Bioinformatic Analysis.

Type 2 diabetes (T2D) patients with SARS-CoV-2 infection hospitalized develop an acute cardiovascular syndrome. It is urgent to elucidate underlying mechanisms associated with the acute cardiac injury in T2D hearts. We performed bioinformatic analysis on the expression profiles of public datasets to identify the pathogenic and prognostic genes in T2D hearts. Cardiac RNA-sequencing datasets from db/db or BKS mice (GSE161931) were updated to NCBI-Gene Expression Omnibus (NCBI-GEO), and used for the transcriptomics analyses with public datasets from NCBI-GEO of autopsy heart specimens with COVID-19 (5/6 with T2D, GSE150316), or dead healthy persons (GSE133054). Differentially expressed genes (DEGs) and overlapping homologous DEGs among the three datasets were identified using DESeq2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were conducted for event enrichment through clusterProfile. The protein-protein interaction (PPI) network of DEGs was established and visualized by Cytoscape. The transcriptions and functions of crucial genes were further validated in db/db hearts. In total, 542 up-regulated and 485 down-regulated DEGs in mice, and 811 up-regulated and 1399 down-regulated DEGs in human were identified, respectively. There were 74 overlapping homologous DEGs among all datasets. Mitochondria inner membrane and serine-type endopeptidase activity were further identified as the top-10 GO events for overlapping DEGs. Cardiac CAPNS1 (calpain small subunit 1) was the unique crucial gene shared by both enriched events. Its transcriptional level significantly increased in T2D mice, but surprisingly decreased in T2D patients with SARS-CoV-2 infection. PPI network was constructed with 30 interactions in overlapping DEGs, including CAPNS1. The substrates Junctophilin2 (Jp2), Tnni3, and Mybpc3 in cardiac calpain/CAPNS1 pathway showed less transcriptional change, although Capns1 increased in transcription in db/db mice. Instead, cytoplasmic JP2 significantly reduced and its hydrolyzed product JP2NT exhibited nuclear translocation in myocardium. This study suggests CAPNS1 is a crucial gene in T2D hearts. Its transcriptional upregulation leads to calpain/CAPNS1-associated JP2 hydrolysis and JP2NT nuclear translocation. Therefore, attenuated cardiac CAPNS1 transcription in T2D patients with SARS-CoV-2 infection highlights a novel target in adverse prognostics and comprehensive therapy. CAPNS1 can also be explored for the molecular signaling involving the onset, progression and prognostic in T2D patients with SARS-CoV-2 infection.

Concurrent diabetes and heart failure: interplay and novel therapeutic approaches.

Diabetes mellitus increases the risk of developing heart failure, and the co-existence of both diseases worsens cardiovascular outcomes, hospitalization, and the progression of heart failure. Despite current advancements on therapeutic strategies to manage hyperglycaemia, the likelihood of developing diabetes-induced heart failure is still significant, especially with the accelerating global prevalence of diabetes and an ageing population. This raises the likelihood of other contributing mechanisms beyond hyperglycaemia in predisposing diabetic patients to cardiovascular disease risk. There has been considerable interest in understanding the alterations in cardiac structure and function in diabetic patients, collectively termed as 'diabetic cardiomyopathy'. However, the factors that contribute to the development of diabetic cardiomyopathies are not fully understood. This review summarizes the main characteristics of diabetic cardiomyopathies, and the basic mechanisms that contribute to its occurrence. This includes perturbations in insulin resistance, fuel preference, reactive oxygen species generation, inflammation, cell death pathways, neurohormonal mechanisms, advanced glycated end-products accumulation, lipotoxicity, glucotoxicity, and post-translational modifications in the heart of the diabetic. This review also discusses the impact of antihyperglycaemic therapies on the development of heart failure, as well as how current heart failure therapies influence glycaemic control in diabetic patients. We also highlight the current knowledge gaps in understanding how diabetes induces heart failure.

Vitamin D Deficiency in Patients with Diabetes in French Guiana: Epidemiology and Relation with Microvascular and Macrovascular Complications.

Vitamin D (VD) insufficiency is common among patients with diabetes in French Guiana. The study aimed to evaluate the prevalence of VD deficiency in the different type of diabetes encountered and to analyze the relationship between VD deficiency and diabetes complications. METHODS: An observational study was conducted between May 2019 and May 2020 in French Guiana, based on data from the CODIAM study (Diabetes Cohort in French Amazonia), describing the characteristics of patients with diabetes mellitus. Among 600 patients enrolled with diabetes, 361 had an available VD assay. RESULTS: The mean 25(OH)VD (hydroxycalciferol) level was 27.9 ng/mL. The level of VD was inversely proportional to the HbA1c (glycated hemoglobin) level. Patients with angina pectoris had a greater proportion of deficiencies VD < 20 ng/mL than those without angina. By contrast, patients with retinopathy had higher vitamin D concentrations than those without retinopathy. There was no association between vitamin D and arteriopathy, stroke, nephropathy and polyneuropathy. VD deficiency was more frequent in women, and in patients with a high school education. CONCLUSION: The prevalence of VD deficiency was high in patients with diabetes in French Guiana, emphasizing the importance of VD supplementation.

Prevalence and Prognostic Implications of Diabetes With Cardiomyopathy in Community-Dwelling Adults.

BACKGROUND: Diabetes is associated with abnormalities in cardiac remodeling and high risk of heart failure (HF). OBJECTIVES: The purpose of this study was to evaluate the prevalence and prognostic implications of diabetes with cardiomyopathy (DbCM) among community-dwelling individuals. METHODS: Adults without prevalent cardiovascular disease or HF were pooled from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], CHS [Cardiovascular Health Study], CRIC [Chronic Renal Insufficiency Cohort]). Among participants with diabetes, DbCM was defined using different definitions: 1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); 2) intermediate restrictive: ≥2 echocardiographic abnormalities; and 3) most restrictive: elevated N-terminal pro-B-type natriuretic peptide levels (>125 in normal/overweight or >100 pg/mL in obese) plus ≥2 echocardiographic abnormalities. Adjusted Fine-Gray models were used to evaluate the risk of HF. RESULTS: Among individuals with diabetes (2,900 of 10,208 included), the prevalence of DbCM ranged from 67.0% to 11.7% in the least and most restrictive criteria, respectively. Higher fasting glucose, body mass index, and age as well as worse kidney function were associated with higher risk of DbCM. The 5-year incidence of HF among participants with DbCM ranged from 8.4%-12.8% in the least and most restrictive definitions, respectively. Compared with euglycemia, DbCM was significantly associated with higher risk of incident HF with the highest risk observed for the most restrictive definition of DbCM (HR: 2.55 [95% CI: 1.69-3.86]; least restrictive criteria HR: 1.99 [95% CI: 1.50-2.65]). A similar pattern of results was observed across cohort studies, across sex and race subgroups, and among participants without hypertension or obesity. CONCLUSIONS: Regardless of the criteria used to define cardiomyopathy, DbCM identifies a high-risk subgroup for developing HF.

Three-Dimensional Global Left Ventricular Myocardial Strain Reduced in All Directions in Subclinical Diabetic Cardiomyopathy: A Systematic Review and Meta-Analysis.

Background Three-dimensional (3D) speckle tracking echocardiography can identify subclinical diabetic cardiomyopathy without geometric assumption and loss of speckle from out-of-plane motions. There is, however, significant heterogeneity among the previous reports. We performed a systematic review and meta-analysis to compare 3D strain values between adults with asymptomatic, subclinical diabetes mellitus (ie, patients with diabetes mellitus without known clinical manifestations of cardiac disease) and healthy controls. Methods and Results After systematic review of 5 databases, 12 valid studies (544 patients with diabetes mellitus and 489 controls) were eligible for meta-analysis. Pooled means and mean difference (MD) using a random-effects model for 3D global longitudinal, circumferential, radial, and area strain were calculated. Patients with diabetes mellitus had an overall 2.31 percentage points lower 3D global longitudinal strain than healthy subjects (16.6%, 95% CI, 15.7-17.6 versus 19.0; 95% CI, 18.2-19.7; MD, -2.31, 95% CI, -2.72 to -2.03). Similarly, 3D global circumferential strain (18.9%; 95% CI, 17.5-20.3 versus 20.5; 95% CI, 18.9-22.1; MD, -1.50; 95% CI, -2.09 to -0.91); 3D global radial strain (44.6%; 95% CI, 40.2-49.1 versus 48.2; 95% CI, 44.7-51.8; MD, -3.47; 95% CI, -4.98 to -1.97), and 3D global area strain (30.5%; 95% CI, 29.2-31.8 versus 32.4; 95% CI, 30.5-34.3; MD, -1.76; 95% CI, -2.74 to -0.78) were also lower in patients with diabetes mellitus. Significant heterogeneity was noted between studies for all strain directions (inconsistency factor [I2], 37%-78%). Meta-regression in subgroup analysis of studies using the most popular vendor found higher prevalence of hypertension as a significant contributor to worse 3D global longitudinal strain. Higher hemoglobulin A1c was the most significant contributor to worse 3D global circumferential strain in patients with diabetes mellitus. Conclusions Three-dimensional myocardial strain was reduced in all directions in asymptomatic diabetic patients. Hypertension and hemoglobin A1c were associated with worse 3D global longitudinal strain and 3D global circumferential strain, respectively. Registration URL: https://www.crd.york.ac.uk/prospero; unique identifier: CRD42020197825.

Diabetic microvascular complications are associated with reduced global longitudinal strain independent of atherosclerotic coronary artery disease in asymptomatic patients with diabetes mellitus: a cross-sectional study.

BACKGROUND: Reduced left ventricular function, assessed by global longitudinal strain (GLS), is sometimes observed in asymptomatic patients with diabetes mellitus (DM) and is often present in patients with diabetes-related microvascular complications. Our aim was to assess the association between microvascular complications, coronary artery plaque burden (PB) and GLS in asymptomatic patients with DM and non-obstructive coronary artery disease (CAD). METHODS: This cross-sectional study included patients with DM without any history, symptoms or objective evidence of obstructive CAD. All patients were identified in the outpatient Clinic of Endocrinology at Odense University Hospital Svendborg. An echocardiography and a coronary computed tomography angiography were performed to assess GLS and the degree of CAD, respectively. A coronary artery stenosis < 50% was considered non-obstructive. A linear regression model was used to evaluate the impact of potential confounders on GLS with adjustment of body mass index (BMI), mean arterial pressure (MAP), microvascular complications, type of diabetes, tissue Doppler average early diastolic mitral annulus velocity (e') and PB. RESULTS: Two hundred and twenty-two patients were included, of whom 172 (77%) had type 2 DM and 50 (23%) had type 1 diabetes. One hundred and eleven (50%) patients had microvascular complications. GLS decreased as the burden of microvascular complications increased (P-trend = 0.01): no microvascular complications, GLS (- 16.4 ± 2.5%), 1 microvascular complication (- 16.0 ± 2.5%) and 2-3 microvascular complications (- 14.9 ± 2.8%). The reduction in GLS remained significant after multivariable adjustment (ß 0.50 [95% CI 0.11-0.88], p = 0.01). BMI (ß 0.12 [95% CI 0.05-0.19]) and MAP (ß 0.05 [95% CI 0.01-0.08]) were associated with reduced GLS. In addition, an increased number of microvascular complications was associated with increased PB (ß 2.97 [95% CI 0.42-5.51], p = 0.02) in a univariable linear regression model, whereas there was no significant association between PB and GLS. CONCLUSIONS: The burden of microvascular complications was associated with reduced GLS independent of other cardiovascular risk factors in asymptomatic patients with DM and non-obstructive CAD. In addition, the burden of microvascular complications was associated with increasing PB, whereas PB was not associated with GLS.

Glucose-lowering Drugs and Hospitalization for Heart Failure: A Systematic Review and Additive-effects Network Meta-analysis With More Than 500 000 Patient-years.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering. PURPOSE: To examine the impact of antihyperglycemic drugs and their association on HHF. DATA SOURCES: Forty randomized controlled trials (RCTs) reporting HHF. STUDY SELECTION: Published RCTs were the data source. DATA EXTRACTION: Incidence rates of HHF. DATA SYNTHESIS: Random additive-effects network meta-analysis showed that metformin (P = 0.55), sulfonylureas (P = 0.51), glucagon-like peptide-1 receptor-agonist (P = 0.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P = 0.54) were neutral on the risk of HHF. SGLT2is and SGLT2is + DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P < 0.0001) and 0.70 (95% CI, 0.60-0.81; P < 0.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZDs) as monotherapy or in combination with DPP4is (HR: 1.45; 95% CI, 1.18-1.78; P = 0.0004) and 1.49 (95% CI, 1.18-1.88; P = 0.0008), respectively. Regardless of the therapy, a 1% reduction in HbA1c reduced the risk of HHF by 31.3% (95% CI, 9-48; P = 0.009). LIMITATIONS: There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. CONCLUSIONS: The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.

Mechanisms of reduced peak oxygen consumption in subjects with uncomplicated type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whose earliest fingerprint is effort intolerance (i.e. impaired peak oxygen consumption, or VO2peak). In the uncomplicated T2D population, however, the prevalence of effort intolerance and the underpinning mechanistic bases are uncertain. Leveraging the multiparametric characterization allowed by imaging-cardiopulmonary exercise testing (iCPET), the aim of this study is to quantify effort intolerance in T2D and to dissect the associated cardiopulmonary alterations. METHODS: Eighty-eight adults with well-controlled and uncomplicated T2D and no criteria for HF underwent a maximal iCPET with speckle tracking echocardiography, vascular and endothelial function assessment, as well as a comprehensive biohumoral characterization. Effort intolerance was defined by a VO2peak below 80% of maximal predicted oxygen uptake. RESULTS: Forty-eight patients (55%) had effort intolerance reaching a lower VO2peak than T2D controls (16.5 ± 3.2 mL/min/kg, vs 21.7 ± 5.4 mL/min/kg, p < 0.0001). Despite a comparable cardiac output, patients with effort intolerance showed reduced peak peripheral oxygen extraction (11.3 ± 3.1 vs 12.7 ± 3.3 mL/dL, p = 0.002), lower VO2/work slope (9.9 ± 1.2 vs 11.2 ± 1.4, p < 0.0001), impaired left ventricle systolic reserve (peak S' 13.5 ± 2.8 vs 15.2 ± 3.0, p = 0.009) and global longitudinal strain (peak-rest ΔGLS 1.7 ± 1.5 vs 2.5 ± 1.8, p = 0.03) than subjects with VO2peak above 80%. Diastolic function, vascular resistance, endothelial function, biohumoral exams, right heart and pulmonary function indices did not differ between the two groups. CONCLUSIONS: Effort intolerance and reduced VO2peak is a severe and highly prevalent condition in uncomplicated, otherwise asymptomatic T2D. It results from a major defect in skeletal muscle oxygen extraction coupled with a subtle myocardial systolic dysfunction.

Association of visit-to-visit glycemic variability with risk of cardiovascular diseases in high-risk Japanese patients with type 2 diabetes: A subanalysis of the EMPATHY trial.

AIMS/INTRODUCTION: Long-term glycemic variability is important for predicting diabetic complications, but evaluation in a Japanese population is lacking. The aim of this study was to explore the relationship between visit-to-visit glycemic variability (VVV) and cardiovascular diseases (CV) in Japanese patients with type 2 diabetes, using the prospective cohort of the EMPATHY trial. MATERIALS AND METHODS: Among 4532 participants with at least three HbA1c measurements, VVV was defined using the coefficient of variation (CV-HbA1c). The outcomes were the composite cardiovascular endpoints, including cardiac, cerebral, renal, and vascular events. The odds ratios (ORs) for the development of outcomes were estimated by using logistic regression models. RESULTS: During a median follow-up of 38 months, 190 subjects developed CV events. The risk of developing CV events increased significantly with increasing quintile of CV-HbA1c, after multivariable adjustment including the mean-HbA1c (OR for the fifth vs first quintile, 1.73; 95%CI, 1.03-2.91; P for trend test = 0.003). There was a stronger association between CV-HbA1c and CV events in patients with a mean-HbA1c of <7% compared with those with a mean-HbA1c of ≥7% (OR per 1 standard deviation, 1.51; 95%CI, 1.23-1.85 and 1.13; 95%CI, 0.98-1.29, respectively; P for interaction = 0.02). CONCLUSIONS: Increases of VVV were associated with the risk of CV events in Japanese patients with type 2 diabetes independent of the mean-HbA1c. The long-term variability of HbA1c as well as the mean HbA1c might be an important glycemic indicator in the management of patients with type 2 diabetes, especially in those with a mean-HbA1c of <7%.

Association between glycemic control and cardiovascular events in older Japanese adults with diabetes mellitus: An analysis of the Japanese medical administrative database.

AIMS/INTRODUCTION: The relationship between glycated hemoglobin (HbA1c) and cardiovascular events in older adults was investigated using a Japanese administrative medical database. MATERIALS AND METHODS: Anonymized medical data on patients with diabetes mellitus aged ≥65 years for the period from January 2010 to December 2019 were extracted from the EBM Provider database. The primary end-point was a composite of cardiovascular events, whereas the other end-points included severe hypoglycemia and fracture. The association between cardiovascular events and HbA1c at the index date (i.e., approximately 10 months after initial diabetes mellitus diagnosis) was evaluated using the Cox proportional hazards model. RESULTS: Among the 3,186,751 patients in the database, 3,946 older adults with diabetes mellitus were eligible for inclusion and were subsequently grouped according to HbA1c quartiles at the index date. Cardiovascular events occurred in 142 patients. Patients with HbA1c in the highest quartile had significantly higher risk of hospitalization for cardiovascular disease than those with HbA1c in the lowest quartile (hazard ratio 1.948; 95% confidence interval 1.252-3.031, P = 0.003). However, the events risk was similar across subgroups with HbA1c <7.2%. The incidence of hypoglycemia and fracture was not significantly associated with the level of glycemic control. CONCLUSIONS: Among older adults with diabetes mellitus, those with poor glycemic control were at higher risk for cardiovascular events compared with those with better glycemic control. However, strict glycemic control had no effect on cardiovascular risk in patients with HbA1c <7.2%.

Heart Failure and Diabetes: Perspective of a Dangerous Association.

The relationship between diabetes and risk of heart failure has been described in previous trials, releasing the importance of the hyperglycemic state that, added to other risk factors, favors the development of coronary heart disease. The mechanism by which, in the absence of hypertension, obesity and/or dyslipidemia, diabetic patients develop cardiomyopathy has been less studied. Recently, the Sodium Glucose Co-transporter type 2 inhibitors (SGLT2 inhibitors) used for the treatment of heart failure patients with or without diabetes has been a breakthrough in the field of medicine. This review describes the established pathophysiology of diabetic cardiomyopathy and SGLT2 inhibitors, their mechanisms of action, and benefits in this group of patients.

High prevalence of fragmented QRS on electrocardiography in Japanese patients with diabetes irrespective of metabolic syndrome.

AIMS/INTRODUCTION: Fragmented QRS (fQRS) on electrocardiography is a marker of myocardial fibrosis and myocardial scar formation. This study aimed to clarify the relationship of fQRS with diabetes mellitus and metabolic syndrome (MetS) in Japanese patients. MATERIALS AND METHODS: Approximately 702 individuals who had a routine health checkup at the Hokuriku Health Service Association (Toyama, Japan) in October 2014 were enrolled and categorized into one of the following four groups based on MetS and diabetes mellitus status: with diabetes mellitus (+) MetS+ (164 participants); diabetes mellitus+ without MetS (Mets-; 103 participants); diabetes mellitus- MetS+ (133 participants); and diabetes mellitus- MetS- (302 participants). fQRS was assessed using the results of electrocardiography. RESULTS: The prevalence of fQRS was statistically higher in patients with diabetes mellitus+ MetS+ (37%) and diabetes mellitus+ MetS- (35%), than those with diabetes mellitus- MetS+ (14%) or diabetes mellitus- MetS- (10%; P < 0.0001). Significant differences were observed between the fQRS(+) and fQRS(-) groups for age, sex, waist circumference, heart rate, hypertension, hemoglobin A1c, total cholesterol, MetS and diabetes mellitus. The area under the receiver operating characteristic curve for traditional risk factors and diabetes mellitus was 0.72 (P = 0.0007, 95% confidence interval 0.67-0.76), and for traditional risk factors and MetS it was 0.67 (P = 0.28, 95% confidence interval 0.62-0.72). Patients with diabetes mellitus had more than threefold higher likelihood of showing fQRS (odds ratio 3.41; 95% confidence interval 2.25-5.22; P < 0.0001) compared with the reference group without diabetes mellitus, after adjusting for age, sex, dyslipidemia, hypertension and waist circumference. CONCLUSIONS: fQRS was observed more frequently in diabetes mellitus patients than in MetS and control individuals. Diabetes mellitus was the most significant determinant for fQRS among MetS and other traditional metabolic risk factors.

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

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.

Cardiac Autonomic Neuropathy is Associated with Improved Diabetic Foot Ulcer Healing: A Single Centre Prospective Cohort Study.

AIMS: People with diabetes and peripheral neuropathy (DPN) are at high risk of diabetic foot ulceration (DFU). The prevalence of cardiac autonomic neuropathy (CAN) in people with DFU is unknown and if CAN influences DFU healing is unclear. METHODS: We investigated, in a prospective observational single-centre cohort study, if CAN predicts DFU healing in 47 (77% male) people with a DFU and DPN attending a university hospital foot clinic. CAN was diagnosed by 2 or more abnormal Ewing's tests. Baseline DFU severity was evaluated using the site, ischaemia, neuropathy, bacterial infection, area and depth (SINBAD) score. The primary outcome was defined as evidence of DFU healing on clinical examination. Median (interquartile) length of follow-up was 1150 (624-1331) days. RESULTS: The prevalence of CAN was 43%. Of the cohort, 70% had complete healing of their DFU. Participants with CAN had a shorter median (interquartile) duration time to heal compared to those without CAN [91 (44-164) days compared to 302 (135-413) (p=0.047)]. Minor/major amputation and mortality was similar in both groups. The presence of CAN increased DFU healing by two-fold [HR=2.05, 95% CI 1.01-4.16, p=0.046] in multivariable competing risk analyses. CONCLUSIONS: We demonstrate a high prevalence of CAN in a DFU cohort and that CAN is associated with improved DFU healing. The results of this study establish the scientific rationale for further studies to better understand the mechanisms between CAN and DFU outcomes.