Effects of dietary interventions and intermittent fasting on HDL function in obese individuals with T2DM: a randomized controlled trial.

BACKGROUND: Cardiovascular disease represents a significant risk factor for mortality in individuals with type 2 diabetes mellitus (T2DM). High-density lipoprotein (HDL) is believed to play a crucial role in maintaining cardiovascular health through its multifaceted atheroprotective effects and its capacity to enhance glycemic control. The impact of dietary interventions and intermittent fasting (IF) on HDL functionality remains uncertain. The objective of this study was to assess the effects of dietary interventions and IF as a strategy to safely improve glycemic control and reduce body weight on functional parameters of HDL in individuals with T2DM. METHODS: Before the 12-week intervention, all participants (n = 41) of the INTERFAST-2 study were standardized to a uniform basal insulin regimen and randomized to an IF or non-IF group. Additionally, all participants were advised to adhere to dietary recommendations that promoted healthy eating patterns. The IF group (n = 19) followed an alternate-day fasting routine, reducing their calorie intake by 75% on fasting days. The participants' glucose levels were continuously monitored. Other parameters were measured following the intervention: Lipoprotein composition and subclass distribution were measured by nuclear magnetic resonance spectroscopy. HDL cholesterol efflux capacity, paraoxonase 1 (PON1) activity, lecithin cholesterol acyltransferase (LCAT) activity, and cholesterol ester transfer protein (CETP) activity were assessed using cell-based assays and commercially available kits. Apolipoprotein M (apoM) levels were determined by ELISA. RESULTS: Following the 12-week intervention, the IF regimen significantly elevated serum apoM levels (p = 0.0144), whereas no increase was observed in the non-IF group (p = 0.9801). ApoM levels correlated with weight loss and fasting glucose levels in the IF group. Both groups exhibited a robust enhancement in HDL cholesterol efflux capacity (p < 0.0001, p = 0.0006) after 12 weeks. Notably, only the non-IF group exhibited significantly elevated activity of PON1 (p = 0.0455) and LCAT (p = 0.0117) following the 12-week intervention. In contrast, the changes observed in the IF group did not reach statistical significance. CONCLUSIONS: A balanced diet combined with meticulous insulin management improves multiple metrics of HDL function. While additional IF increases apoM levels, it does not further enhance other aspects of HDL functionality. TRIAL REGISTRATION: The study was registered at the German Clinical Trial Register (DRKS) on 3 September 2019 under the number DRKS00018070.

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.

Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action.

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.

Estimated glomerular filtration rate slope and risk of primary and secondary major adverse cardiovascular events and heart failure hospitalization in people with type 2 diabetes: An analysis of the EXSCEL trial.

AIM: The decline in estimated glomerular filtration rate (eGFR), a significant predictor of cardiovascular disease (CVD), occurs heterogeneously in people with diabetes because of various risk factors. We investigated the role of eGFR decline in predicting CVD events in people with type 2 diabetes in both primary and secondary CVD prevention settings. MATERIALS AND METHODS: Bayesian joint modelling of repeated measures of eGFR and time to CVD event was applied to the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial to examine the association between the eGFR slope and the incidence of major adverse CV event/hospitalization for heart failure (MACE/hHF) (non-fatal myocardial infarction, non-fatal stroke, CV death, or hospitalization for heart failure). The analysis was adjusted for age, sex, smoking, systolic blood pressure, baseline eGFR, antihypertensive and lipid-lowering medication, diabetes duration, atrial fibrillation, high-density cholesterol, total cholesterol, HbA1c and treatment allocation (once-weekly exenatide or placebo). RESULTS: Data from 11 101 trial participants with (n = 7942) and without (n = 3159) previous history of CVD were analysed. The mean ± SD eGFR slope per year in participants without and with previous CVD was -0.68 ± 1.67 and -1.03 ± 2.13 mL/min/1.73 m2, respectively. The 5-year MACE/hHF incidences were 7.5% (95% CI 6.2, 8.8) and 20% (95% CI 19, 22), respectively. The 1-SD decrease in the eGFR slope was associated with increased MACE/hHF risks of 48% (HR 1.48, 95% CI 1.12, 1.98, p = 0.007) and 33% (HR 1.33, 95% CI 1.18,1.51, p < 0.001) in participants without and with previous CVD, respectively. CONCLUSIONS: eGFR trajectories over time significantly predict incident MACE/hHF events in people with type 2 diabetes with and without existing CVD, with a higher hazard ratio for MACE/hHF in the latter group.

Metabolic risk factor targets in relation to clinical characteristics and comorbidities among individuals with type 2 diabetes treated in primary care - The countrywide cross-sectional AUSTRO-PROFIT study.

AIMS: This study assessed the achievement rates of metabolic risk factor targets and their association with clinical characteristics and comorbidities among individuals with type 2 diabetes (T2D) treated in the primary care in Austria. MATERIALS AND METHODS: A countrywide cross-sectional study, the AUSTRO-PROFIT, was conducted in Austria from 2021 to 2023 on 635 individuals with T2D. Metabolic risk factor targets were defined as the percentage of people achieving low-density lipoprotein cholesterol (LDL-C) <70 mg/dL (or < 55 mg/dL if cardiovascular or microvascular disease was present), glycated haemoglobin (HbA1c) <7% (53 mmol/mol) and blood pressure < 140/90 mmHg. RESULTS: The mean age of the participants was 65.7 ± 11.2 years; the median duration of T2D was 8 (4-14) years; and 58.7% of the participants were male. The percentages of participants achieving LDL-C, HbA1c, blood pressure and all targets were 44%, 53%, 57% and 13%, respectively. Older age, longer T2D duration, cardiovascular disease and microvascular complications were associated with suboptimal achievement of metabolic risk factor targets. CONCLUSIONS: The AUSTRO-PROFIT study revealed notable variations in metabolic targets achievement with respect to clinical characteristics and comorbidities. These findings underscore the importance of establishing national diabetes registries and implementing multifactorial targeted and individualized interventions to further improve the quality of T2D care in primary care settings in Austria.

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.

Physiologically Achievable Concentration of 2-Deoxy-D-Glucose Stimulates IFN-γ Secretion in Activated T Cells In Vitro.

2-deoxy-D-glucose (2DG) is a glycolysis and protein N-glycosylation inhibitor with promising anti-tumor and immunomodulatory effects. However, 2DG can also suppress T cell function, including IFN-γ secretion. Few human T cell studies have studied low-dose 2DG, which can increase IFN-γ in a Jurkat clone. We therefore investigated 2DG's effect on IFN-γ in activated human T cells from PBMCs, with 2DG treatment commenced either concurrently with activation or 48 h after activation. Concurrent 2DG treatment decreased IFN-γ secretion in a dose-dependent manner. However, 2DG treatment of pre-activated T cells had a hormetic effect on IFN-γ, with 0.15-0.6 mM 2DG (achievable in vivo) increasing and >2.4 mM 2DG reducing its secretion. In contrast, IL-2 levels declined monotonously with increasing 2DG concentration. Lower 2DG concentrations reduced PD-1 and increased CD69 expression regardless of treatment timing. The absence of increased T-bet or Eomes expression or IFNG transcription suggests another downstream mechanism. 2DG dose-dependently induced the unfolded protein response, suggesting a possible role in increased IFN-γ secretion, possibly by increasing the ER folding capacity for IFN-γ via increased chaperone expression. Overall, low-dose, short-term 2DG exposure could potentially improve the T cell anti-tumor response.

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.

SGLT2 Inhibition in Acute Myocardial Infarction-A Comprehensive Review.

In heart failure as well as in chronic kidney disease sodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the landscape of medical therapy. Originally developed for use in diabetes, an unforeseen cardiovascular benefit extended SGLT2 inhibitor use from antihyperglycemic agents to cardiovascular and renal risk modifying agents. As their benefit in cardiovascular disease is independent from the diabetic state as well as the left ventricular ejection fraction it is the only class of therapy recommended throughout the spectrum of heart failure. Until very recently, the remaining gap in evidence has been data on the safety and efficacy of SGLT2 inhibitors in patients with acute myocardial infarction (MI) as former trials of SGLT2 inhibitors to date have excluded patients with recent ischemic events. As the first out of three trials conducted in post MI SGLT2 inhibitors therapy the EMMY trial was published. EMMY randomized 476 patients shortly after percutaneous intervention for recent large MI to either 10 mg of empagliflozin daily or placebo. The primary endpoint of changes in N-terminal pro brain natriuretic peptide (NT-proBNP) over 26 weeks as well as the functional and structural secondary endpoints were met. This provides first evidence of SGLT2 inhibitors-mediated beneficial results in this group of patients. We here discuss these results in the light of the two upcoming outcome trials (DAPA-MI and EMPACT-MI) with regard to the future role of this class of drugs early after MI.

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.