Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have been suggested to exert cardioprotective effects in patients with heart failure, possibly by improving the metabolism of ketone bodies in the myocardium. METHODS: This post hoc analysis of the EMMY trial investigated the changes in serum ß-hydroxybutyrate (3-ßOHB) levels after acute myocardial infarction (AMI) in response to 26-week of Empagliflozin therapy compared to the usual post-MI treatment. In addition, the association of baseline and repeated measurements of 3-ßOHB with cardiac parameters and the interaction effects of Empagliflozin were investigated. Cardiac parameters included N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricle end-systolic volume (LVESV), left ventricle end-diastolic volume (LVEDV), and left ventricular filling pressure (E/é ratio). RESULTS: The mean 3-ßOHB levels increased from baseline (46.2 ± 3.0 vs. 51.7 ± 2.7) to 6 weeks (48.8 ± 2.2 vs. 42.0 ± 2.3) and 26 weeks (49.3 ± 2.2 vs. 35.8 ± 1.9) in the Empagliflozin group compared to a consistent decline in placebo over 26 weeks (pinteraction < 0.001). Baseline and longitudinal measurements of 3-ßOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-ßOHB value was negatively associated with LVEF (coefficient: - 0.464, 95%CI - 0.863;- 0.065, p = 0.023), while an increase in its levels over time was positively associated with LVEF (0.595, 0.156;1.035, 0.008). The baseline 3-ßOHB was positively associated with LVESV (1.409, 0.186;2.632, 0.024) and LVEDV (0.640, - 1.170;- 2.449, 0.488), while an increase in its levels over time was negatively associated with these cardiac parameters (LVESV: - 2.099, - 3.443;- 0.755, 0.002; LVEDV: - 2.406, - 4.341;- 0.472, 0.015). Empagliflozin therapy appears to modify the association between 3-ßOHB, LVEF (pinteraction = 0.090), LVESV (pinteraction = 0.134), and LVEDV (pinteraction = 0.168), particularly at 26 weeks; however, the results were not statistically significant. CONCLUSION: This post hoc analysis showed that SGLT2i increased 3-ßOHB levels after AMI compared to placebo. Higher baseline 3-ßOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-ßOHB levels over time improved these markers. This highlights the importance of investigating ketone body metabolism in different post-MI phases. Although more pronounced effect of 3-ßOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect.

Glycated haemoglobin, HOMA2-B, C-peptide to glucose ratio and type 2 diabetes clusters as predictors for therapy failure in individuals with type 2 diabetes without insulin therapy: A registry analysis.

AIM: Some people with type 2 diabetes mellitus (T2D) and declining ß-cell function do require insulin over time. Various laboratory parameters, indices of glucose metabolism or phenotypes of T2D (clusters) have been suggested, which might predict future therapy failure (TF), indicating the need for insulin therapy initiation. This analysis evaluated glycated haemoglobin (HbA1c), homeostatic model assessment (HOMA)2-B, C-peptide to glucose ratio (CGR) and diabetes clusters as predictive parameters for the occurrence of glycaemic TF in individuals diagnosed with T2D without previous insulin therapy. MATERIALS AND METHODS: In total, 159 individuals with T2D [41% female, median age 50 (IQR: 53-69) years, diabetes duration 9 (5-15) years], without insulin therapy were prospectively evaluated for the occurrence of a composite primary endpoint, including HbA1c increasing or remaining >8.0% (64 mmol/mol) 3 months after baseline on non-insulin glucose-lowering agents, insulin initiation or hospital admissions because of acute hyperglycaemic events. Diabetes clusters were formed according to previously described characteristics. Only severe autoimmune diabetes clusters were excluded because of a small amount of glutamate decarboxylase antibody-positive participants. The other clusters were distributed as mild age-related diabetes 33%; severe insulin-deficient diabetes 31%; mild obesity-related diabetes 20%; and severe insulin-resistant diabetes 15%. RESULTS: During a median observation of 57 months, higher tertiles of HbA1c at baseline, HOMA2-B, as well as a lower CGR were significantly predictive for the occurrence of the primary endpoint. The probability of meeting the primary endpoint was the highest for mild obesity-related diabetes [hazard ratio 3.28 (95% confidence interval 1.75-6.2)], followed by severe insulin-deficient diabetes [hazard ratio 2.03 (95% confidence interval 1.1-3.7)], mild age-related diabetes and the lowest for severe insulin-resistant diabetes. The best performance to predict TF with an area under the curve (AUC) of 0.77 was HbA1c at baseline, followed by HOMA2-B (AUC 0.69) and CGR (AUC 0.64). CONCLUSION: HbA1c, indices of insulin secretion capacity (HOMA2-B and CGR) and T2D clusters might be applicable tools to guide practitioners in the decision of whether insulin is required in people already diagnosed with T2D. These findings need to be validated in prospective studies.

Impact of a 4-week intensive track and field training intervention on glycaemia in adolescents with type 1 diabetes: The ChilDFiT1 study.

AIM: To investigate the safety and efficacy of track and field training compared with intensification of insulin treatment only in adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: Eighteen adolescents (seven females) with T1D were included (age 15.1 ± 1.1 years, HbA1c 7.3% ± 1.0% [56.3 ± 10.9 mmol/mol]). After a 4-week observational control phase, participants were randomized to either stand-alone intensive glycaemic management (IT; telemedicine or on-site visits, three times/week) or additionally performed track and field exercise (EX; three 60-minute sessions/week) for 4 weeks. Glycaemia was assessed via continuous glucose monitoring during observational control and intervention phases. RESULTS: Time in range (70-180 mg/dL; 3.9-10.0 mmol/L) significantly improved from the observational control phase to the exercise intervention phase in EX (69% ± 13% vs. 72% ± 11%, P = .049), but not in IT (59% ± 22% vs. 62% ± 16%, P = .399). Time below range 1 (54-69 mg/dL; < 3.9 mmol/L) improved in IT (3.1% ± 1.9% vs. 2.0% ± 0.8%, P = .017) and remained stable in EX (2.0% ± 1.7 vs. 1.9% ± 1.1%, P = .999). The EX group's HbA1c ameliorated preintervention to postintervention (mean difference: ΔHbA1c -0.19% ± 0.17%, P = .042), which was not seen within the IT group (ΔHbA1c -0.16% ± 0.37%, P = .40). Glucose standard deviation was reduced significantly in EX (55 ± 11 vs. 51 ± 10 mg/dL [3.1 ± 0.6 vs. 2.8 ± 0.6 mmol/L], P = .011), but not in IT (70 ± 24 vs. 63 ± 18 mg/dL [3.9 ± 1.3 vs. 3.5 ± 1.0 mmol/L], P = .186). CONCLUSION: Track and field training combined with intensive glycaemic management improved glycaemia in adolescents with T1D, which was not observed in the non-exercise group.

Pre-Transplant Frequencies of FoxP3+CD25+ in CD3+CD8+ T Cells as Potential Predictors for CMV in CMV-Intermediate Risk Kidney Transplant Recipients.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100 IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1 year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

Alterations in trimethylamine-N-oxide in response to Empagliflozin therapy: a secondary analysis of the EMMY trial.

INTRODUCTION: The relationship between sodium glucose co-transporter 2 inhibitors (SGLT2i) and trimethylamine N-oxide (TMAO) following acute myocardial infarction (AMI) is not yet explored. METHODS: In this secondary analysis of the EMMY trial (ClinicalTrials.gov registration: NCT03087773), changes in serum TMAO levels were investigated in response to 26-week Empagliflozin treatment following an AMI compared to the standard post-MI treatment. Additionally, the association of TMAO changes with clinical risk factors and cardiorenal biomarkers was assessed. RESULTS: The mean age of patients (N = 367) was 57 ± 9 years, 82% were males, and 14% had type 2 diabetes. In the Empagliflozin group, the median TMAO value was 2.62 µmol/L (IQR: 1.81) at baseline, 3.74 µmol/L (2.81) at 6 weeks, and 4.20 µmol/L (3.14) at 26 weeks. In the placebo group, the median TMAO value was 2.90 µmol/L (2.17) at baseline, 3.23 µmol/L (1.90) at 6 weeks, and 3.35 µmol/L (2.50) at 26 weeks. The serum TMAO levels increased significantly from baseline to week 6 (coefficient: 0.233; 95% confidence interval 0.149-0.317, p < 0.001) and week 26 (0.320, 0.236-0.405, p < 0.001). The average increase in TMAO levels over time (pinteraction = 0.007) was significantly higher in the Empagliflozin compared to the Placebo group. Age was positively associated with TMAO, whereas eGFR and LVEF were negatively associated with TMAO. CONCLUSIONS: Our results are contrary to existing experimental studies that showed the positive impact of SGLT2i on TMAO precursors and cardiovascular events. Therefore, we recommend further research investigating the impact of SGLT2i therapy on acute and long-term changes in TMAO in cardiovascular cohorts.

Time-dependent event accumulation in a cardiovascular outcome trial of patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

BACKGROUND: Estimating cardiovascular (CV) event accrual is important for outcome trial planning. Limited data exist describing event accrual patterns in patients with type 2 diabetes (T2D). We compared apparent CV event accrual patterns with true event rates in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). METHODS: Centrally adjudicated event dates and accrual rates for a 4-point major adverse CV event composite (MACE-4; includes CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina hospitalization), MACE-4 components, all-cause mortality (ACM), and heart failure hospitalization were compiled. We used three graphical methods (Weibull probability plot, plot of negative log of the Kaplan-Meier survival distribution estimate, and the Epanechnikov kernel-smoothed estimate of the hazard rate) to examine hazard rate morphology over time for the 7 outcomes. RESULTS: Plots for all outcomes showed real-time constant event hazard rates for the duration of the follow-up, confirmed by Weibull shape parameters. The Weibull shape parameters for ACM (1.14, 95% CI 1.08-1.21) and CV death (1.08, 95% CI 1.01-1.16) were not sufficiently > 1 as to require non-constant hazard rate models to accurately depict the data. The time lag between event occurrence and event adjudication being completed, the adjudication gap, improved over the course of the trial. CONCLUSIONS: In TECOS, the nonfatal event hazard rates were constant over time. Small increases over time in the hazard rate for fatal events would not require complex modelling to predict event accrual, providing confidence in traditional modelling methods for predicting CV outcome trial event rates in this population. The adjudication gap provides a useful metric to monitor within-trial event accrual patterns. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00790205.

Impact of the SGLT2-inhibitor empagliflozin on inflammatory biomarkers after acute myocardial infarction - a post-hoc analysis of the EMMY trial.

BACKGROUND: SGTL2-inhibitors are a cornerstone in the treatment of heart failure, but data on patients with acute myocardial infarction (AMI) is limited. The EMMY trial was the first to show a significant reduction in NTproBNP levels as well as improved cardiac structure and function in post-AMI patients treated with Empagliflozin compared to placebo. However, data on the potential impact of SGLT2-inhibitors on inflammatory biomarkers after AMI are scarce. MATERIALS AND METHODS: The EMMY trial is an investigator-initiated, multicentre, double-blind, placebo-controlled trial, which enrolled patients after AMI, receiving either 10 mg Empagliflozin once daily or placebo over a period of 26 weeks on top of standard guideline-recommended therapy starting within 72 h after percutaneous coronary intervention. In this post-hoc subgroup analysis of the EMMY trial, we investigated inflammatory biomarkers of 374 patients. The endpoints investigated were the mean change in inflammatory biomarkers such as high-sensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), neutrophils, leukocytes, neutrophile/lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) from baseline to 26 weeks. RESULTS: Baseline median (interquartile ranges) IL-6 was 17.9 pg/mL (9.0-38.7), hsCRP 18.9 mg/L (11.2-37.1), neutrophil count 7.9 x G/L (6.2-10.1), leukocyte count 10.8 x G/L (9.1-12.8) and neutrophile/lymphocyte ratio (NLR) of 0.74 (0.67-0.80). At week 26, a significant mean reduction in inflammatory biomarkers was observed, being 35.1 ± 3.2% (p < 0.001) for IL-6, 57.4 ± 0.7% (p < 0.001) for hsCRP, 26.1 ± 0.7% (p < 0.001) for neutrophils, 20.5 ± 0.6% (p < 0.001) for leukocytes, 10.22 ± 0.50% (p < 0.001) for NLR, and - 2.53 ± 0.92% for PLR (p = 0.006) with no significant difference between Empagliflozin and placebo treatment. CONCLUSION: Trajectories of inflammatory biomarkers showed a pronounced decline after AMI, but Empagliflozin treatment did not impact this decline indicating no central role in blunted systemic inflammation mediating beneficial effects.

Timing of SGLT2i initiation after acute myocardial infarction.

BACKGROUND: Pharmacological post-MI treatment is routinely initiated at intensive/cardiac care units. However, solid evidence for an early start of these therapies is only available for dual platelet therapy and statins, whereas data on beta blockers and RAAS inhibitors are heterogenous and mainly limited to STEMI and heart failure patients. Recently, the EMMY trial provided the first evidence on the beneficial effects of SGLT2 inhibitors (SGLT2i) when initiated early after PCI. In patients with type 2 diabetes mellitus, SGLT2i are considered "sick days drugs" and it, therefore, remains unclear if very early SGLT2i initiation following MI is as safe and effective as delayed initiation. METHODS AND RESULTS: The EMMY trial evaluated the effect of empagliflozin on NT-proBNP and functional and structural measurements. Within the Empagliflozin group, 22 (9.5%) received early treatment (< 24 h after PCI), 98 (42.2%) within a 24 to < 48 h window (intermediate), and 111 (48.1%) between 48 and 72 h (late). NT-proBNP levels declined by 63.5% (95%CI: - 69.1; - 48.1) in the early group compared to 61.0% (- 76.0; - 41.4) in the intermediate and 61.9% (- 70.8; - 45.7) in the late group (n.s.) within the Empagliflozin group with no significant treatment groups-initiation time interaction (pint = 0.96). Secondary endpoints of left ventricular function (LV-EF, e/e`) as well as structure (LVESD and LVEDD) were also comparable between the groups. No significant difference in severe adverse event rate between the initiation time groups was detected. CONCLUSION: Very early administration of SGLT2i after acute myocardial infarction does not show disadvantageous signals with respect to safety and appears to be as effective in reducing NT-proBNP as well as improving structural and functional LV markers as initiation after 2-3 days.

A pilot study: Exploring the influence of COVID-19 on cardiovascular physiology and retinal microcirculation.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the cardiovascular system. The current study investigated changes in heart rate (HR), blood pressure (BP), pulse wave velocity (PWV), and microcirculation in patients recovering from Coronavirus disease 2019 (COVID-19) infection. METHODOLOGY: Out of 43 initially contacted COVID-19 patients, 35 (30 males, 5 females; age: 60 ± 10 years; and body mass index (BMI): 31.8 ± 4.9) participated in this study. Participants were seen on two occasions after hospital discharge; the baseline measurements were collected, either on the day of hospital discharge if a negative PCR test was obtained, or on the 10th day after hospitalization if the PCR test was positive. The second measurements were done 60 days after hospitalization. The vascular measurements were performed using the VICORDER® device and a retinal blood vessel image analysis. RESULTS: A significant increase in systolic BP (SBP) (from 142 mmHg, SD: 15, to 150 mmHg, SD: 19, p = 0.041), reduction in HR (from 76 bpm, SD: 15, to 69 bpm, SD: 11, p = 0.001), and narrower central retinal vein equivalent (CRVE) (from 240.94 µm, SD: 16.05, to 198.05 µm, SD: 17.36, p = 0.013) were found. Furthermore, the trends of increasing PWV (from 11 m/s, SD: 3, to 12 m/s, SD: 3, p = 0.095) and decreasing CRAE (from 138.87 µm, SD: 12.19, to 136.77 µm, SD: 13.19, p = 0.068) were recorded. CONCLUSION: The present study investigated cardiovascular changes following COVID-19 infection at two-time points after hospital discharge (baseline measurements and 60 days post-hospitalization). Significant changes were found in systolic blood pressure, heart rate, and microvasculature indicating that vascular adaptations may be ongoing even weeks after hospitalization from COVID-19 infection. Future studies could involve conducting additional interim assessments during the active infection and post-infection periods.

Blood glucose response to running or cycling in individuals with type 1 diabetes: A systematic review and meta-analysis.

AIMS: The aim of this systematic review and meta-analysis was to assess how running and cycling influence the magnitude of blood glucose (BG) excursions in individuals with type 1 diabetes. METHODS: A systematic literature search was conducted in EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and ISI Web of Knowledge for publications from January 1950 until February 2021. Parameters included for analysis were population (adults and adolescents), exercise type, intensity, duration and insulin preparation. The meta-analysis was performed to estimate the pooled mean with a 95% confidence interval (CI) of delta BG levels. In addition, sub-group and meta-regression analyses were performed to assess the influence of these parameters on delta BG. RESULTS: The database search identified 3192 articles of which 69 articles were included in the meta-analysis. Due to crossover designs within articles, 151 different results were included for analysis. Data from 1901 exercise tests of individuals with type 1 diabetes with a mean age of 29 ± 4 years were included. Overall, exercise tests BG decreased by -3.1 mmol/L [-3.4; -2.8] within a mean duration of 46 ± 21 min. The pooled mean decrease in BG for running was -4.1 mmol/L [-4.7; -2.4], whilst the pooled mean decrease in BG for cycling was -2.7 mmol/L [-3.0; -2.4] (p < 0.0001). Overall results can be found in Table S2. CONCLUSIONS: Running led to a larger decrease in BG in comparison to cycling. Active individuals with type 1 diabetes should be aware that current recommendations for glycaemic management need to be more specific to the mode of exercise.

Joint longitudinal and time-to-event modelling compared with standard Cox modelling in patients with type 2 diabetes with and without established cardiovascular disease: An analysis of the EXSCEL trial.

AIM: To demonstrate the gain in predictive performance when cardiovascular disease (CVD) risk prediction tools (RPTs) incorporate repeated rather than only single measurements of risk factors. MATERIALS AND METHODS: We used data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to compare the quality of predictions of future major adverse cardiovascular events (MACE) with the Cox proportional hazards model (using single values of risk factors) compared to the Bayesian joint model (using repeated measures of risk factors). The risk of MACE was calculated in patients with type 2 diabetes with and without established CVD. We assessed the predictive ability of the following cardiovascular risk factors: glycated haemoglobin, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, estimated glomerular filtration rate, low-density lipoprotein cholesterol (LDL-C), total cholesterol, and systolic blood pressure (SBP) using the time-dependent area under the receiver-operating characteristic curve (aROC) for discrimination and the time-dependent Brier score for calibration. RESULTS: In participants without history of CVD, the aROC of SBP increased from 0.62 to 0.69 when repeated rather than only single measurements of SBP were incorporated into the predictive model. Similarly, the aROC increased from 0.67 to 0.80 when repeated rather than only single measurements of both SBP and LDL-C were incorporated into the predictive model. For all other investigated cardiovascular risk factors, the measures of discrimination and calibration both improved when using the joint model as compared to the Cox proportional hazards model. The improvement was evident in participants with and without history of CVD but was more pronounced in the latter group. CONCLUSIONS: The analysis demonstrates that the joint modelling approach, considering trajectories of cardiovascular risk factors, provides superior predictive performance compared to standard RPTs that use only a single timepoint.

Impact of severe hypoglycaemia requiring hospitalization on mortality in people with type 1 diabetes: A national retrospective observational cohort study.

AIMS: To assess if the risk of all-cause mortality increases in people with type 1 diabetes (T1D) with increasing number of severe hypoglycaemia episodes requiring hospitalization. MATERIALS AND METHODS: We conducted a national retrospective observational cohort study in people with T1D (diagnosed between 2000 and 2018). Clinical, comorbidity and demographic variables were assessed for impact on mortality for people with no, one, two and three or more episodes of severe hypoglycaemia requiring hospitalization. The time to death (all-cause mortality) from the timepoint of the last episode of severe hypoglycaemia was modelled using a parametric survival model. RESULTS: A total of 8224 people had a T1D diagnosis in Wales during the study period. The mortality rate (95% confidence interval [CI]) was 6.9 (6.1-7.8) deaths/ 1000 person-years (crude) and 15.31 (13.3-17.63) deaths/ 1000 person-years (age-adjusted) for those with no occurrence of severe hypoglycaemia requiring hospitalization. For those with one episode of severe hypoglycaemia requiring hospitalization the mortality rate (95% CI) was 24.9 (21.0-29.6; crude) and 53.8 (44.6-64.7) deaths/ 1000 person-years (age-adjusted), for those with two episodes of severe hypoglycaemia requiring hospitalization it was 28.0 (23.1-34.0; crude) and 72.8 (59.2-89.5) deaths/ 1000 person-years (age-adjusted), and for those with three or more episodes of severe hypoglycaemia requiring hospitalization it was 33.5 (30.0-37.3; crude) and 86.3 (71.7-103.9) deaths/ 1000 person years (age-adjusted; P < 0.001). A parametric survival model showed that having two episodes of severe hypoglycaemia requiring hospitalization was the strongest predictor for time to death (accelerated failure time coefficient 0.073 [95% CI 0.009-0.565]), followed by having one episode of severe hypoglycaemia requiring hospitalization (0.126 [0.036-0.438]) and age at most recent episode of severe hypoglycaemia requiring hospitalization (0.917 [0.885-0.951]). CONCLUSIONS: The strongest predictor for time to death was having two or more episodes of severe hypoglycaemia requiring hospitalization.

Empagliflozin in acute myocardial infarction: the EMMY trial.

AIMS: Sodium-glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking. METHODS AND RESULTS: In this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 IU/L) were randomly assigned to empagliflozin 10 mg or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757-2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower [95% confidence interval (CI) -4.4% to -23.6%] after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2-2.9%, P = 0.029), mean E/e' reduction was 6.8% (95% CI 1.3-11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (95% CI 3.4-11.5 mL, P = 0.0003) and 9.7 mL (95% CI 3.7-15.7 mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups. CONCLUSION: In patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters. CLINICALTRIALS.GOV REGISTRATION: NCT03087773.

Comparative Analysis of Predictive Interstitial Glucose Level Classification Models.

BACKGROUND: New methods of continuous glucose monitoring (CGM) provide real-time alerts for hypoglycemia, hyperglycemia, and rapid fluctuations of glucose levels, thereby improving glycemic control, which is especially crucial during meals and physical activity. However, complex CGM systems pose challenges for individuals with diabetes and healthcare professionals, particularly when interpreting rapid glucose level changes, dealing with sensor delays (approximately a 10 min difference between interstitial and plasma glucose readings), and addressing potential malfunctions. The development of advanced predictive glucose level classification models becomes imperative for optimizing insulin dosing and managing daily activities. METHODS: The aim of this study was to investigate the efficacy of three different predictive models for the glucose level classification: (1) an autoregressive integrated moving average model (ARIMA), (2) logistic regression, and (3) long short-term memory networks (LSTM). The performance of these models was evaluated in predicting hypoglycemia (<70 mg/dL), euglycemia (70-180 mg/dL), and hyperglycemia (>180 mg/dL) classes 15 min and 1 h ahead. More specifically, the confusion matrices were obtained and metrics such as precision, recall, and accuracy were computed for each model at each predictive horizon. RESULTS: As expected, ARIMA underperformed the other models in predicting hyper- and hypoglycemia classes for both the 15 min and 1 h horizons. For the 15 min forecast horizon, the performance of logistic regression was the highest of all the models for all glycemia classes, with recall rates of 96% for hyper, 91% for norm, and 98% for hypoglycemia. For the 1 h forecast horizon, the LSTM model turned out to be the best for hyper- and hypoglycemia classes, achieving recall values of 85% and 87% respectively. CONCLUSIONS: Our findings suggest that different models may have varying strengths and weaknesses in predicting glucose level classes, and the choice of model should be carefully considered based on the specific requirements and context of the clinical application. The logistic regression model proved to be more accurate for the next 15 min, particularly in predicting hypoglycemia. However, the LSTM model outperformed logistic regression in predicting glucose level class for the next hour. Future research could explore hybrid models or ensemble approaches that combine the strengths of multiple models to further enhance the accuracy and reliability of glucose predictions.

Albumin of People with Diabetes Mellitus Is More Reduced at Low HbA1c.

Oxidative stress is involved in the development, progression, and complications of diabetes mellitus (DM). Oxidative modification of human serum albumin's cysteine-34 is a marker for oxidative stress-related pathological conditions. We aimed to evaluate the redox state of albumin in patients with DM to investigate possible correlations with age, diabetes duration, and disease control status. Plasma aliquots were collected from 52 participants (26 type 1 and 26 type 2 DM). Patients were divided into two groups according to their glycated hemoglobin levels less than or equal to and greater than 58 mmol/L. Albumin redox state was assessed with high-performance liquid chromatography by fractionating it into human mercaptalbumin (HMA) and human nonmercaptalbumin 1 and 2 (HNA1 and HNA2). Albumin redox fractions were differently related to the age of study participants. In age-matched T1DM and T2DM groups, the albumin redox state was essentially the same. Irreversibly oxidized HNA2 was positively correlated with diabetes duration, especially in the T1DM group. HNA was increased in people with an increased HbA1c (>58 mmol/mol). Our results support the hypothesis that oxidative stress plays a crucial role in DM pathogenesis and emphasize the importance of diabetes control on systemic oxidative burden.

Changes in Lipoprotein(a) Levels in People after ST Elevation Myocardial Infarction-The STEMI-Lipids Study.

Lipoprotein(a) (Lp(a)) is considered an independent risk factor for cardiovascular diseases. The plasma concentration of Lp(a) is largely genetically determined but varies over a wide range within the population. This study investigated changes in Lp(a) levels after an acute myocardial infarction. Patients who underwent coronary angiography due to an ST elevation myocardial infarction were enrolled (n = 86), and Lp(a) levels were measured immediately after the intervention, one day, two days, and at a post-discharge follow-up visit at 3 to 6 months after the acute myocardial infarction. Median Lp(a) levels increased from a median of 7.9 mg/dL (3.8-37.1) at hospital admission to 8.4 mg/dL (3.9-35.4) on the following day, then to 9.3 mg/dL (3.7-39.1) on day two (p < 0.001), and to 11.2 mg/dL (4.4-59.6) at the post-discharge follow-up (p < 0.001). Lp(a) levels were the lowest during the acute myocardial infarction and started to increase significantly immediately thereafter, with the highest levels at the post-discharge follow-up. The moderate but significant increase in Lp(a) in people with acute myocardial infarction appears to be clinically relevant on an individual basis, especially when specific Lp(a) cut-off levels are supposed to determine the initiation of future treatment. Hence, a repeated measurement of Lp(a) after myocardial infarction should be performed.

Ertugliflozin to reduce arrhythmic burden in ICD/CRT patients (ERASe-trial) - A phase III study.

Sodium glucose cotransporter 2 (SGLT2) have proven profound positive effects in heart failure with reduced ejection fraction (HFrEF). These effects are independent from the presence of diabetes. Metabolic effects, antiinflammatory, and antifibrotic properties are discussed as underlying mechanisms. Despite a strong correlation of ventricular arrhythmias with HFrEF, the impact of ertugliflozin on the ventricular arrhythmic burden has not been investigated, yet. Therefore, the Ertugliflozin to Reduce Arrhythmic burden in ICD ± CRT patientS (ERASe) trial was designed to investigate the efficacy and safety of ertugliflozin in patients with reduced and midrange ejection fraction (EF) with or without diabetes. METHODS: Within a multicentre, national, randomized, double-blind, placebo-controlled, phase 3b trial we aim to enrol a total of 402 patients across Austria. Patients with reduced or midrange EF and ICD ± CRT therapy >3 months and previous ventricular tachycardia (at least 10 documented VT episodes within the last 12 months) are randomized in a 1:1 ratio to ertugliflozin (5 mg once daily orally administered) or matching placebo. The primary endpoint of the ERASe trial is to investigate the impact of ertugliflozin on total burden of ventricular arrhythmias. Further objectives will include number of therapeutic interventions of implanted devices, atrial fibrillation and heart failure biomarkers. CONCLUSION: The ERASe trial will be the first trial to test ertugliflozin in heart failure patients with nonpreserved ejection fraction and ongoing ICD ± CRT therapy regardless of their diabetic status. The ERASe trial may therefore extend the concept of SGLT2 inhibition to improve cardiac remodelling, including reduced arrhythmic burden. Trial registration Identifier EudraCT Nr. 2020-002581-14 / ClinicalTrials.gov Identifier: NCT04600921.

Alteration of circulating platelet-related and diabetes-related microRNAs in individuals with type 2 diabetes mellitus: a stepwise hypoglycaemic clamp study.

BACKGROUND: In patients with type 2 diabetes mellitus (T2DM) an association between severe hypoglycaemic episodes and the risk of cardiovascular (CV) morbidity and mortality has been previously established. METHODS: We aimed to investigate the influence of hypoglycaemia on several diabetes-related and platelet-related miRNAs selected based on bioinformatic analysis and literature search, including hsa-miR-16, hsa-miR-34a, hsa-miR-129-2, hsa-miR-15a, hsa-miR-15b, hsa-miR-106a, miR-223, miR-126. Selected miRNAs were validated by qRT-PCR in 14 patients with T2DM on metformin monotherapy, without established CV disease and antiplatelet therapy during a stepwise hypoglycaemic clamp experiment and a follow-up 7 days after the clamp event. In order to identify which pathways and phenotypes are associated with validated miRNAs we performed target prediction on genes expressed with high confidence in platelets. RESULTS: Circulating levels of miR-106a-5p, miR-15b, miR-15a, miR-16-5p, miR-223 and miR-126 were increased after euglycaemic clamp followed by hypoglycaemic clamp, each with its distinctive time trend. On the contrary, miR-129-2-3p, miR-92a-3p and miR-34a-3p remained unchanged. MiR-16-5p was negatively correlated with interleukin (IL)-6, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) (p = 0.002, p < 0.001, p = 0.016, respectively), whereas miR-126 was positively correlated with VCAM (p < 0.001). There were negative correlations between miR-16-5p, miR-126 and coagulation factors, including factor VIII and von Willebrand factor (vWF). Among all studied miRNAs, miR-126, miR-129-2-3p and miR-15b showed correlation with platelet function. Bioinformatic analysis of platelet-related targets of analyzed miRNAs showed strong enrichment of IL-2 signaling. We also observed significant enrichment of pathways and diseases related to cancer, CV diseases, hyperglycemia, and neurological diseases. CONCLUSIONS: Hypoglycaemia can significantly influence the expression of platelet-enriched miRNAs, with a time trend paralleling the time course of platelet activation. This suggests miRNAs could be exploited as biomarkers for platelet activation in response to hypoglycaemia, as they are probably released by platelets upon activation by hypoglycaemic episodes. Should they hold their promise in clinical endpoint studies, platelet-derived miRNAs might become helpful markers of CV risk in subjects with diabetes. Trial registration The study was registered at clinical trials.gov; Impact of Hypoglycaemia in Patients With DIAbetes Mellitus Type 2 on PLATElet Activation (Diaplate), trial number: NCT03460899.

INTERmittent FASTing in people with insulin-treated type 2 diabetes mellitus - the INTERFAST-2 study protocol.

AIM: Intermittent fasting, a dietary intervention of alternate eating and fasting, has gained popularity in people trying to lose weight. Intermittent fasting could provide an alternative to classic caloric restriction in people with type 2 diabetes mellitus. The aim of the study is to determine the impact of a 12-week intermittent fasting regimen compared with usual care in people with type 2 diabetes mellitus receiving insulin therapy. METHODS: This open, single-centre, randomized controlled trial investigates participants with type 2 diabetes mellitus on insulin therapy and a glycated haemoglobin A1c (HbA1c) of ≥53 mmol/mol (≥7.0%) and a minimum insulin dose of 0.3 IU/kg body weight per day. Participants are randomized in a 1:1 ratio to either 12 weeks of intermittent fasting or the standard care group. All participants receive dietary counselling, continuous glucose monitoring, measurement of the resting metabolic rate, an oral glucose tolerance test, body composition measurement via dual-energy X-ray absorptiometry and stool samples for microbiome analyses at the beginning and at the end of the intervention. Two co-primary outcomes (analysed in hierarchical order) were chosen for the study: (i) the difference in the change of HbA1c from baseline to 12 weeks and (ii) the difference in the number of participants achieving a combined end point encompassing a body weight reduction of at least 2%, an insulin dose reduction of at least 10% and an absolute HbA1c reduction of at least 3 mmol/mol (0.3%) between the two groups.

Performance of intermittently scanned continuous glucose monitoring systems in people with type 1 diabetes: A pooled analysis.

AIMS: To conduct a pooled analysis to assess the performance of intermittently scanned continuous glucose monitoring (isCGM) in association with the rate of change in sensor glucose in a cohort of children, adolescents, and adults with type 1 diabetes. MATERIAL AND METHODS: In this pooled analysis, isCGM system accuracy was assessed depending on the rate of change in sensor glucose. Clinical studies that have been investigating isCGM accuracy against blood glucose, accompanied with collection time points were included in this analysis. isCGM performance was assessed by means of median absolute relative difference (MedARD), Parkes error grid (PEG) and Bland-Altman plot analyses. RESULTS: Twelve studies comprising 311 participants were included, with a total of 15 837 paired measurements. The overall MedARD (interquartile range) was 12.7% (5.9-23.5) and MedARD differed significantly based on the rate of change in glucose (P < 0.001). An absolute difference of -22 mg/dL (-1.2 mmol/L) (95% limits of agreement [LoA] 60 mg/dL (3.3 mmol/L), -103 mg/dL (-5.7 mmol/L)) was found when glucose was rapidly increasing (isCGM glucose minus reference blood glucose), while a -32 mg/dL (1.8 mmol/L) (95% LoA 116 mg/dL (6.4 mmol/L), -51 mg/dL (-2.8 mmol/L)) absolute difference was observed in periods of rapidly decreasing glucose. CONCLUSIONS: The performance of isCGM was good when compared to reference blood glucose measurements. The rate of change in glucose for both increasing and decreasing glucose levels diminished isCGM performance, showing lower accuracy during high rates of glucose change.