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Diabetes is a major risk factor for cardiovascular diseases, and myocardial damage caused by hyperglycemia is the main cause of heart failure. However, there is still a lack of systematic understanding of myocardial damage caused by diabetes. At present, we believe that the cellular inflammatory damage caused by hyperglycemia is one of the causes of diabetic cardiomyopathy. Pyroptosis, as a proinflammatory form of cell death, is closely related to the occurrence and development of diabetic cardiomyopathy. Therefore, this paper focuses on the important role of inflammation in the occurrence and development of diabetic cardiomyopathy. From the perspective of pyroptosis, we summarize the pyroptosis of different types of cells in diabetic cardiomyopathy and its related signaling pathways. It also summarizes the treatment of diabetic cardiomyopathy, hoping to provide methods for the prevention and treatment of diabetic cardiomyopathy by inhibiting pyroptosis., Competing Interests: Declaration of competing interest All other authors declared no potential competing interest relevant to the authorship and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: FDA-approved drug labels are an important source of information for clinicians who prescribe medications for treatment of diabetes. We reviewed drug labels to (1) understand the landscape of classes of medications approved for type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), (2) explore the indications and safety information and (3) examine their cardiovascular safety., Methods: We searched four public references and reviewed all FDA-approved labels for "indication and usage," "adverse effects," "warnings and precautions," and "cardiovascular outcomes" from October 1982 to July 2016. We also reviewed FDA drug-safety communications from January 2015 to May 2017., Results: The labels reveal 12 classes of medications approved for T2DM with only 2 classes approved for T1DM. There is emerging evidence about cardiovascular safety and risk reduction from diabetes medications which is now being incorporated in drug labels., Conclusions: All currently available diabetes medications are approved for adults with T2DM with a remarkably limited number for adults with T1DM and children with T1DM or T2DM. The incorporation of emerging data on cardiovascular outcomes in FDA drug labels is expected to influence the way physicians treat patients with diabetes., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: We investigated the efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF)., Methods: Data for patients randomized to dapagliflozin 10mg or placebo with a history of HF were pooled from five clinical trials. HbA 1c , weight and systolic blood pressure (SBP; two studies) were examined up to 52weeks using longitudinal repeated-measures models. Composite cardiovascular outcomes, hospitalizations for HF (HHF), and adverse events (AEs) were also assessed., Results: Patients (mean age 64years, T2DM duration ~14years, HbA 1c 8.2%, ~50% with New York Heart Association Class ≥II) received dapagliflozin (N=171) or placebo (N=149). Dapagliflozin produced clinically meaningful placebo-adjusted reductions in HbA 1c (-0.55%; 95% confidence interval [CI]: -0.80, -0.30), weight (-2.67kg; 95% CI: -3.88, -1.47), and SBP (-2.05mmHg; 95% CI: -5.68, 1.57) over 52weeks. HHF was rare, but numerically lower with dapagliflozin (n=1 [0.6%]) vs placebo (n=7 [4.7%]). Point estimates for hazard ratios of composite cardiovascular outcomes favored dapagliflozin vs placebo, although 95% CIs crossed unity., Conclusions: Dapagliflozin produced clinically meaningful reductions in HbA 1c , weight, and SBP in patients with T2DM and HF, and was well tolerated., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Type 2 diabetes is associated with cardiovascular complications. It is largely unknown which patients have poor treatment response and high complication risk; biomarkers are studied for this purpose. The aim of the study was to investigate the association between clinical factors such as HbA1c, level of biomarkers (C-peptide, copeptin) at diagnosis and changes in HbA1c, blood pressure or body mass index (BMI) after five years., Methods: Clinical data and blood samples from 460 newly diagnosed type 2 diabetes patients from the Skaraborg diabetes register (SDR) at diagnosis and after 5years and were analyzed with linear and logistic regressions., Results: High BMI at diagnosis and smoking were associated with less reduction of HbA1c i.e. poorer treatment outcome after 5years. A high HbA1c at baseline predicted a greater reduction of HbA1c and need for insulin treatment. High systolic blood pressure and BMI at baseline were associated with greater reduction. The biomarkers were not associated with increase of blood pressure, HbA1c, BMI or need for insulin treatment., Conclusions: Smokers and patients with high HbA1c at diagnosis respond poorer to treatment over 5years. This highlights the importance of advice for non-smoking and weight reduction and more intensive treatment over time., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Predicting incident diabetes could inform treatment strategies for diabetes prevention, but the incremental benefit of recalculating risk using updated risk factors is unknown. We used baseline and 1-year data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial to compare diabetes risk prediction using historical or updated clinical information., Methods: Among non-diabetic participants reaching 1year of follow-up in NAVIGATOR, we compared the performance of the published baseline diabetes risk model with a "landmark" model incorporating risk factors updated at the 1-year time point. The C-statistic was used to compare model discrimination and reclassification analyses to demonstrate the relative accuracy of diabetes prediction., Results: A total of 7527 participants remained non-diabetic at 1year, and 2375 developed diabetes during a median of 4years of follow-up. The C-statistic for the landmark model was higher (0.73 [95% CI 0.72-0.74]) than for the baseline model (0.67 [95% CI 0.66-0.68]). The landmark model improved classification to modest (<20%), moderate (20%-40%), and high (>40%) 4-year risk, with a net reclassification index of 0.14 (95% CI 0.10-0.16) and an integrated discrimination index of 0.01 (95% CI 0.003-0.013)., Conclusions: Using historical clinical values to calculate diabetes risk reduces the accuracy of prediction. Diabetes risk calculations should be routinely updated to inform discussions about diabetes prevention at both the patient and population health levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: The association between blood glucose fluctuation and poststroke cardiovascular outcome has been largely unknown. This study attempted to evaluate whether initial glycemic variability increases cardiovascular events and mortality in diabetic patients with acute ischemic stroke., Methods: We recruited consecutive patients with acute ischemic stroke or transient ischemic attack from March 2005 to December 2014. A total of 674 patients with diabetes within 72 hours from stroke onset were included. The serum glucose levels were checked 4 times per day during the initial 3 hospital days. J-index, coefficients of variation and standard deviation were calculated for glycemic variability. Composite outcome (nonfatal stroke, nonfatal myocardial infarction, cardiovascular death) and all-cause mortality at 3 months were prospectively captured. Multivariable logistic regression analyses were done adjusting for covariates which can influence on cardiovascular outcomes., Results: Cardiovascular composite outcomes at 3 months were identified in 71 (10.5%): 11 (6.5%), 15 (8.9%), 18 (10.7%) and 27 (16.0%) in each J-index quartiles (P = .035). The highest quartile of J-index had significantly higher cardiovascular death (4.2%, 3.6%, 6.5% and 11.8%; P = .008). In multivariable logistic regression, age (odds ratio [OR] 1.045; 95% confidence interval [CI] 1.006-1.084), P = .021), NIH stroke scale (OR 1.078; 95% CI 1.024-1.134, P = .004), and the highest J-index (OR 12.058; 95% 1.890-76.912, P = .008) were significantly associated with 3-month cardiovascular composite outcome. Increased cardiovascular outcomes in highest J-index quartile were similar in both euglycemic and hyperglycemic groups., Conclusion: The initial glycemic variability might increase cardiovascular events in acute ischemic stroke patients with diabetes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The field of type 2 diabetes is undergoing a major transformation. Recent cardiovascular outcomes trials of glucose-lowering agents - including EMPA-REG, IRIS and LEADER, have all demonstrated convincing cardiovascular benefits within a relatively short period of time - all likely driven via non-glycemic effects of compounds under study. The implications of these studies (with primary focus on the LEADER trial) - and how their result may be paradigm shifting for type 2 diabetes management, are discussed in this article., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims/hypothesis: To determine the association between inpatient glycemic variability and long-term mortality in patients with type 2 diabetes mellitus., Methods: Capillary blood glucose (CBG) of inpatients from 8 hospitals was analysed. 28,353 admissions identified were matched for age, duration of diabetes and admission and median and interquartile range of CBG. 6year mortality was investigated for (i) those with CBG IQR in the top half of all IQR measurements (matched for all except IQR), vs those in the lower half and (ii) those with the lowest quartile median glucose (matched for all except median)., Results: CONCLUSION: Higher inpatient glycemic variability is associated with increased mortality on long-term follow up. When matched by IQR, we have demonstrated higher median CBG is associated with lower long-term mortality. CBG variability may increase cardiovascular morbidity by increasing exposure to hypoglycaemia or to variability per se. In hospitalized patients with diabetes, glycemic variability should be minimised and when greater CBG variability is unavoidable, a less stringent CBG target considered., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Exercise is recommended as a cornerstone of treatment for type 2 diabetes mellitus (T2DM), however, it is often poorly adopted by patients. Even in the absence of apparent cardiovascular disease, persons with T2DM have an impaired ability to carry out maximal and submaximal exercise and these impairments are correlated with cardiac and endothelial dysfunction. Glucagon-like pepetide-1 (GLP-1) augments endothelial and cardiac function in T2DM. We hypothesized that administration of a GLP-1 agonist (exenatide) would improve exercise capacity in T2DM., Methods and Results: Twenty-three participants (64±4years; mean±SE) with uncomplicated T2DM were randomized in a double-blinded manner to receive either 10μg BID of exenatide or matching placebo after baseline measurements. Treatment with exenatide did not improve VO 2peak (P=0.1464) or VO 2 kinetics (P=0.2775). Diastolic function, assessed via resting lateral E:E', was improved with administration of exenatide compared with placebo (Placebo Pre: 7.6±1.0 vs. Post: 8.4±1.2 vs. Exenatide Pre: 8.1±0.7 vs. Post: 6.7±0.6; P=0.0127). Additionally, arterial stiffness measured by pulse wave velocity, was reduced with exenatide treatment compared with placebo (Placebo Pre: 10.5±0.8 vs. Post: 11.5±1.1s vs. Exenatide Pre: 11.4±1.8 vs. Post: 10.2±1.4s; P=0.0373). Exenatide treatment did not improve endothelial function (P=0.1793)., Conclusions: Administration of exenatide improved cardiac function and reduced arterial stiffness, however, these changes were not accompanied by improved functional exercise capacity. In order to realize the benefits of this drug on exercise capacity, combining exenatide with aerobic exercise training in participants with T2DM may be warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: Endothelial dysfunction, vascular inflammation and oxidative stress have been integrally linked to the pathogenesis of both type 2 diabetes and cardiovascular disease. Aged Garlic Extract (AGE), a potent antioxidant, has been shown in previous studies to attenuate these novel risk factors in a non-diabetic population., Aims: This study tested the hypothesis that AGE may improve endothelial function, oxidative stress, vascular inflammation and insulin resistance in high risk cardiovascular subjects with type 2 diabetes., Methods: A double blind, placebo controlled crossover pilot study was performed in 26 subjects with type 2 diabetes who received 1200 mg of AGE or placebo daily for 4 weeks with a 4 week washout period. Plasma HsCRP was measured as a marker of inflammation. Plasma TAOS, blood GSH/GSSG and plasma LHP were measured as markers of oxidative stress/anti-oxidant defense. Insulin resistance was measured using the HOMA-IR method. Endothelial function was measured using change in the reflective index (RI) post-salbutamol using digital photoplethysmography and urinary albumin/creatinine ratio was measured as a biochemical surrogate. Measurements were taken at baseline and after intervention with AGE or placebo., Results: Of the 26 patients studied (male 17, female 9), age was 61 ± 8 years (mean ± 1 SD), HbA1c 7.2 ± 1.1%, BP 130/75 ± 15.9/9.8 mmHg, total cholesterol 4.2 ± 0.81 mmol/l, triglyceride 2.11 ± 1.51 mmol/l, and HDL cholesterol 1.04 ± 0.29 mmol/l. The majority of patients were being treated with metformin (59%), aspirin (50%) and statin (96%) therapy. 36% were treated with an ACEI. There were no changes in these therapies throughout the study. Treatment with AGE had no significant effect upon the above metabolic parameters including insulin resistance. Treatment with AGE also had no significant effect on markers of endothelial function (plethysmography), oxidative stress (TAOS, GSH/GSSG, LHP) or inflammation (HsCRP)., Conclusion: In this group of type 2 diabetic patients at high cardiovascular risk, 4 weeks treatment with AGE did not significantly improve endothelial function, vascular inflammation, oxidative stress or insulin resistance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Heart rate corrected QT (QTc) interval prolongation is a risk factor associated with increased mortality. Hyperbaric oxygen therapy (HBO) has previously been shown to have acute beneficial effects on QTc dispersion. The aim of this study was to evaluate long-term effects of HBO on QTc time in diabetic patients with hard-to-heal foot ulcers., Methods: In a prospective, double-blinded placebo-controlled study, patients were randomized to 40 treatment sessions with either HBO or air (placebo), at 2.5 ATA. Patients fulfilling >35 completed treatment sessions were included in the evaluation., Results: Of the initial 75 patients (38 HBO/37 placebo), two were excluded due to pacemaker use. Baseline characteristics were similar between groups. At the 2-year follow-up, QTc time was significantly shorter in the HBO compared to the placebo group (438 vs. 453ms, p<0.05). Further, fewer HBO treated patients had a QTc time >450ms (22 vs. 53 %, p<0.02). This difference seemed to be caused by a significant prolongation of the QTc interval in the placebo group (427 (419-459) at baseline vs. 456ms (424-469) after 2years), whereas no significant change was seen in HBO treated patients., Conclusions: HBO treatment might protect against QTc prolongation in this high-risk diabetic population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: To determine whether visit-to-visit blood pressure (BP) variability can predict cardiovascular disease (CVD) incidence in type 2 diabetes patients independently of mean BP, and to analyze the time-to-effect relationship between BP and CVD risk., Methods: We retrospectively enrolled 629 type 2 diabetes patients with no history of CVD who first visited our hospital between 1995 and 1996, made at least one hospital visit per year, were followed-up for at least 1 year, and had undergone four or more BP measurements. The patients were followed until June 2012 at the latest., Results: CVD occurred in 66 patients. Variability in systolic or diastolic BP (SBP and DBP, respectively) was a significant predictor of CVD incidence, independent of mean SBP or DBP. CVD incidence was significantly associated with SBP during the preceding 3-5 years, with the highest risk occurring during the preceding 3 years., Conclusions: Visit-to-visit BP variability independently predicts CVD incidence in type 2 diabetes patients. Increased SBP over the preceding 3-5 years indicated a significant CVD risk. To prevent CVD, BP management should focus on stable and well-timed control. In particular, BP stabilization at an early phase and BP control during late phases are important., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD)., Methods: Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use., Results: Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78-1.05) or repaglinide use (aHR 0.80; 95% CI 0.63-1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome., Conclusions: In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The role of peroxisome proliferator-activated receptor alpha (PPARα) in the development of myocardial lipotoxicity is widely observed in diabetic disorders. Thus, we investigated if treatment of Astragalus polysaccharides modulates lipotoxic cardiomyopathy both in vivo and in vitro through PPARα mechanisms., Methodology/principal Findings: The effects of Astragalus polysaccharides (APS) on PPARα target gene expression and protein levels were tested in vitro and in vivo, including in mice with PPARα cardiac-restricted overexpression [myosin heavy chain (MHC)-PPARα] and in H9c2 embryonic rat cardiomyocytes with or without PPARα agonist. Echocardiographic studies, analyses of myocardial triglyceride and cardiac fuel utilization analyses were also performed in MHC-PPARα mice. Treatment with APS prevented myocardial triglyceride accumulation and cardiac dysfunction in the MHC-PPARα mice, with the normalization of energy metabolic derangements in hearts including reduced free fatty acids utilization and increased glucose uptake. Consistently, both in the MHC-PPARα hearts and H9c2 cardiomyocytes with PPARα agonist, the activation of PPARα gene regulatory pathway involved in FFA-oxidation was down-regulated by APS treatment, while the suppression of PPARα target genes involved in glucose uptake and oxidation was normalized by APS administration., Conclusions: Therapy with APS could prevent the development of lipotoxic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARα-mediated regulatory pathways., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sudden cardiac death (SCD) affects a significant percentage of diabetic patients. SCD in these patients can be due to several factors, such as diastolic dysfunction, heart failure, altered platelet function, inflammation, sympathetic nervous stimulation and other factors. In the present review, we discuss the association between diabetes mellitus and SCD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: The cost implications of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial were evaluated using a prespecified analysis plan., Methods: Purchasing power parity-adjusted country-specific costs were applied to consumed healthcare resources by participants from each country. Subgroup analyses were conducted on subgroups based on baseline metabolic status and diabetes duration., Results: The total undiscounted cost per participant in the insulin glargine arm was $13,491 ($13,080 to $14,254) versus $11,189 ($10,568 to $12,147) for standard care, an increase of $2303 ($1370 to $3235; p < 0.0001); the discounted increase was $2099 ($1276 to $2923; P < 0.0001). The greater number of mainly generic oral anti-diabetic agents in the standard group partially offset the higher cost of basal insulin glargine. As the trial progressed and the standard group required more anti-diabetic medications, the annual cost difference decreased, reaching $68 (-$160 to $295) in the last year. The subgroup whose baseline diabetes duration was ≥ 6 years achieved cost-savings during the trial., Conclusions: From a global perspective basal insulin glargine use in ORIGIN incurred greater costs than standard care using older generic drugs. Nevertheless, the cost difference fell with time such that the intervention was cost-neutral by the last year., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Type 2 diabetes mellitus (T2DM) significantly increases morbidity and mortality from cardiovascular disease (CVD). Treatments for patients with T2DM have the potential to reduce cardiovascular (CV) risk. This review focuses on the potential of a new class of antidiabetic agents, the sodium glucose cotransporter 2 (SGLT2) inhibitors, to reduce CV risk in patients with T2DM through reductions in hyperglycemia, blood pressure (BP), and body weight. The results of clinical trials of SGLT2 inhibitors are summarized and discussed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aims: Data on glucose and cardiovascular disease (CVD) risk factor control among persons with type 2 diabetes mellitus (DM) according to insulin treatment status are lacking. We examined DM control, risk factors, and comorbidities among U.S. persons according to insulin treatment status., Methods: In the U.S. National Health and Nutrition Examination Surveys 2003-2006, we examined in 10,637 adults aged ≥30 with type 2 DM the extent of control of A1c, LDL-C, HDL-C, triglycerides, and blood pressure (BP) and composite goal attainment by insulin use status., Results: 6.6% (n=889, projected to 14.3 million) had type 2 DM; of these, 22.9% were insulin users and 57.2% were treated only by other diabetes medications. Overall, 58.2% had an A1c<7% (53 mmol/mol) (insulin users 33.1%, non-insulin treated 66.1%, and 77.9% of those not on medication, p<0.0001). Overall, 44.2% were at a BP goal of <130/80 mmHg, 43.8% had an LDL-C<100 mg/dl (2.6 mmol/L), and 13.9% a BMI<25 kg/m(2). Only 10.2% were simultaneously at A1c, LDL, and BP goals (5.4% of those on insulin)., Conclusions: U.S. adults with type 2 DM, especially those treated with insulin remain inadequately controlled for A1c and CVD risk factors and have a high prevalence of comorbidities., (Copyright © 2012 Elsevier Inc. All rights reserved.)