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Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial pleiotropic effects, contributing to improved cardiovascular and renal outcomes for patients with and without diabetes. The impact of SGLT2is on arrhythmic burden remains largely unexplored through randomized trials., Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, we investigated the effects of ertugliflozin on arrhythmic burden among patients with heart failure with an ejection fraction less than 50%. All patients had an implantable cardioverter-defibrillator (ICD) with or without a cardiac resynchronization therapy device (CRT-D) and were randomized (1:1) to receive either ertugliflozin 5 mg once daily or placebo. The primary end point was the number of incident sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation events from baseline to week 52. Secondary end points included the total number of non-sustained ventricular tachycardias, appropriate ICD therapies, changes in N-terminal pro-brain-type natriuretic peptide (NTproBNP) levels, and the number of heart failure hospitalizations., Results: Randomization was prematurely terminated, after class IA guideline recommendations were published for SGLT2is in patients with heart failure regardless of the ejection fraction. The final analysis included 46 patients (11% of the originally planned sample size). The yearly rate of the primary end point was 3.5 (95% confidence interval [CI] 2.8 to 4.4) with ertugliflozin compared with 13.3 with placebo (95% CI 11.8 to 14.8; rate ratio 0.16, 95% CI 0.04 to 0.61; P<0.001). There were no apparent differences in appropriate ICD therapies, hospitalizations, NTproBNP levels, or predefined adverse and serious adverse events., Conclusions: Ertugliflozin reduced sustained ventricular tachycardia or ventricular fibrillation events in adults with heart failure and an ICD compared with placebo; however, our trial ended early and thus results should be interpreted with caution. (Funded by Investigator-initiated Studies Program of Merck Sharp & Dohme Corp and Pfizer; EudraCT number, 2020-002581-14; ClinicalTrials.gov number NCT04600921.).

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., (© 2024. The Author(s).)

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 β-hydroxybutyrate (3-βOHB) 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-βOHB 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-βOHB 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 (p interaction  < 0.001). Baseline and longitudinal measurements of 3-βOHB were not significantly associated with NT-proBNP and E/é ratio. Baseline 3-βOHB 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-βOHB 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-βOHB, LVEF (p interaction  = 0.090), LVESV (p interaction  = 0.134), and LVEDV (p interaction  = 0.168), particularly at 26 weeks; however, the results were not statistically significant., Conclusion: This post hoc analysis showed that SGLT2i increased 3-βOHB levels after AMI compared to placebo. Higher baseline 3-βOHB levels were inversely associated with cardiac function at follow-up, whereas a sustained increase in 3-βOHB 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-βOHB on cardiac markers was observed in the SGLT2i group, further research is required to explore this interaction effect., (© 2024. The Author(s).)

Objective: Women have a higher comorbidity burden and a lower survival rate after acute myocardial infarction (AMI) than men. This analysis aimed to investigate the impact of sex on the effect of treatment with the sodium glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin immediately after an AMI., Methods: Participants were randomized to either empagliflozin or placebo and followed for 26 weeks after initiating the treatment no later than 72 hours after a percutaneous coronary intervention following an AMI. We analyzed the impact of sex on the beneficial effects of empagliflozin observed for heart failure biomarkers as well as structural and functional cardiac parameters., Results: Women had higher NT-proBNP levels at baseline (median 2117pg/mL, IQR 1383-3267 pg/mL versus 1137 pg/mL, IQR 695-2050 pg/mL; p < 0.001) and were older than men (median 61y, IQR 56-65y versus 56y, IQR 51-64y, p = 0.005). The beneficial effects of empagliflozin on NT-proBNP levels (P interaction  = 0.984), left ventricular ejection fraction (P interaction  = 0.812), left ventricular end systolic volume (P interaction  = 0.183), or left ventricular end diastolic volume (P interaction  = 0.676) were independent of sex., Conclusions: Empagliflozin exhibited similar benefits in women and men when administered immediately after an AMI., Competing Interests: Declaration of competing interest H.S. is on the advisory board and speaker's bureau of Boehringer Ingelheim, NovoNordisk, Sanofi-Aventis, Amgen, AstraZeneca, Bayer, Eli Lilly, Kapsch, MSD, and Daiichi Sankyo. DvL is on the advisory board and speaker's bureau of Boehringer Ingelheim, Novartis, Sanova, Sanofi, Orion, AstraZeneca, Bayer Recardio, Vaxxinity, and Daiichi Sankyo. FA reports no conflict of interest related to this study., (Copyright © 2023 Hellenic Society of Cardiology. Published by Elsevier Inc. All rights reserved.)

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 (p int  = 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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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 (p interaction  = 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., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

Aims: In the ULTRAFLEXI-1 study, we compared basal insulin Glargine 300 U/mL (IGlar U300) and insulin Degludec 100 U/mL (IDeg U100) for time below range <70 mg/dL (TBR <70 ; 3.9 mmol/L) in two different doses (100% and 75% of the regular dose) when used around spontaneous exercise sessions in adults with type 1 diabetes. Methods: A randomized, single-center, four-period, cross-over trial was performed and in each of the four 2-weeks-periods, participants attended six spontaneous 60 min moderate-intensity evening cycle ergometer exercise sessions. The basal insulin administered on the exercise days were IGlar U300 100% or 75% of the regular dose or IDeg U100 100% or 75%, respectively (morning injection). The primary outcome was the TBR <70 during the 24 h postexercise periods of the six spontaneous exercise sessions in the four trial arms and was analyzed in hierarchical order using the repeated measures linear mixed model. Results: Twenty-five people with type 1 diabetes were enrolled (14 males) with a mean age of 41.4 ± 11.9 years and an HbA 1c of 7.5% ± 0.8% (59 ± 9 mmol/mol). The mean ± standard error of mean TBR <70 during the 24 h periods following the exercise sessions was 2.71% ± 0.51% for IGlar U300 (100%) and 4.37% ± 0.69% for IDeg U100 (100%) ( P  = 0.023) as well as 2.28% ± 0.53% for IGlar U300 and 2.55% ± 0.58% for IDeg U100 when using a 75% dose on exercise days ( P  = 0.720). Time in glucose range 70-180 was the highest in the IDeg U100 (100%) group. Conclusions: TBR <70 within the first 24 h after spontaneous exercise sessions was significantly lower when receiving IGlar U300 compared to IDeg U100 when a regular basal dose was administered.

Objective: To investigate the safety and feasibility of 3 nonconsecutive days of intermittent fasting (IF) per week over 12 weeks in participants with insulin-treated type 2 diabetes., Research Design and Methods: Forty-six people were randomized to an IF or control group. Dietary counseling and continuous glucose monitoring was provided. Coprimary end points were the change in HbA1c from baseline to 12 weeks and a composite end point (weight reduction ≥2%, insulin dose reduction ≥10%, and HbA1c reduction ≥3 mmol/mol)., Results: The IF group showed a significant HbA1c reduction (-7.3 ± 12.0 mmol/mol) compared with the control group (0.1 ± 6.1 mmol/mol) over 12 weeks (P = 0.012). The coprimary end point was achieved by 8 people in the IF and none in the control group (P < 0.001). No severe hypoglycemia occurred., Conclusions: IF is a safe and feasible dietary option to ameliorate glycemic control while reducing total daily insulin dose and body weight in insulin-treated people with type 2 diabetes., (© 2023 by the American Diabetes Association.)

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting ( p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.

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., Competing Interests: Conflict of interest: H.S. is on the advisory board and speakers bureau of by Boehringer Ingelheim, NovoNordisk, Sanofi-Aventis, Amgen, AstraZeneca, Bayer, Eli Lilly, Kapsch, MSD, and Daiichi Sankyo. D.V.L. is on the advisory board and speakers’ bureau of Abiomed, AstraZeneca, Bayer, Daiichi Sankyo, Orion, Sanofi, and Servier and receives consulting fees from Recardio Inc, Bayer, TLL, Vaxxinity Inc. P.M.Z. received speaker fees from AstraZeneca, Pfizer, Medtronic, and Boehringer Ingelheim. R.R.H. reports research support from AstraZeneca, Bayer and Merck Sharp & Dohme, and personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis, and Novo Nordisk. M.W. receives speaker fees from Bayer, Novartis and consulting fees from Radcliff Cardiology. A.Z. receives fees from Boehringer Ingelheim, AstraZeneca, NovoNordisk, Bayer, Daiichi Sankyo, Amgen, and Sanofi. C.R. receives payment or Honoria for lectures from Boehringer Ingelheim, Pfizer, and AstraZeneca and support for attending meetings from Boehringer Ingelheim and Pfizer. T.R.P. receives consulting fees and payment of honoraria for lectures from Arecor and Novo Nordisk and grants from Arecor, Sanofi, and Novo Nordisk. H.A. receives Honoria for lectures from Boehringer Ingelheim and AstraZeneca and financial support for attending meetings and transport from Boehringer Ingelheim and AstraZeneca. P.A. reports speakers’ fee from Bayer and Pfizer. J.M.S.M. received speaker or consultant fees from Chiesi, Boehringer Ingelheim, Biosensors, P&F, Gruenenthal, Bayer, Medtronic, and Boston Scientific within the last 3 years. D.M. receives consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, and Vifor, further he receives payment for lectures from AstraZeneca, Bayer, Boehringer Ingelheim, Vifor, and BMS. C.H.S. reports grants and consulting fees from AstraZeneca, Boehringer Ingelheim, and MSD. M.L. receives consulting fees from Johnson and Johnson and support for attending meetings from MSD. R.B. received a grant from Abbott and speaker or consultant fees from Abbott, Amgen, AstraZeneca, Biotronik, Bayer, Boehringer Ingelheim, Novartis, and Vivorpharma within the last 3 years. The remaining authors have no relevant conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

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., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

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., (© 2022. The Author(s).)

Aims: To investigate the seroconversion following first and second COVID-19 vaccination in people with type 1 and type 2 diabetes in relation to glycaemic control prior to vaccination and to analyse the response in comparison to individuals without diabetes., Materials and Methods: This prospective, multicentre cohort study analysed people with type 1 and type 2 diabetes and a glycated haemoglobin level ≤58 mmol/mol (7.5%) or >58 mmol/mol (7.5%), respectively, and healthy controls. Roche's Elecsys anti-SARS-CoV-2 S immunoassay targeting the receptor-binding domain was used to quantify anti-spike protein antibodies 7 to 14 days after the first and 14 to 21 days after the second vaccination., Results: A total of 86 healthy controls were enrolled in the study, as well as 161 participants with diabetes, of whom 150 (75 with type 1 diabetes and 75 with type 2 diabetes) were eligible for the analysis. After the first vaccination, only 52.7% of participants in the type 1 diabetes group and 48.0% of those in the type 2 diabetes group showed antibody levels above the cut-off for positivity. Antibody levels after the second vaccination were similar in participants with type 1 diabetes, participants with type 2 diabetes and healthy controls after adjusting for age, sex and multiple testing (P > 0.05). Age (r = -0.45, P < 0.001) and glomerular filtration rate (r = 0.28, P = 0.001) were significantly associated with antibody response., Conclusions: Anti-SARS-CoV-2 S receptor-binding domain antibody levels after the second vaccination were comparable in healthy controls and in participants with type 1 and type 2 diabetes, irrespective of glycaemic control. Age and renal function correlated significantly with the extent of antibody levels., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Prolonged fasting has shown beneficial effects in healthy individuals and in people with chronic diseases. In type 1 diabetes, the effect or even the feasibility of fasting is unclear. We aimed to assess the impact and safety of prolonged fasting in adults with type 1 diabetes. Glycemia was assessed during overnight fasting (12 hours) vs. prolonged fasting (36 hours) via an intermittently-scanned continuous glucose monitoring system. Anthropometric data, metabolic and hormonal markers were compared between both trial arms. After each fasting period, a 75 g oral glucose tolerance test was performed and plasma glucose levels and hormones were assessed. Data were compared via paired t-tests and mixed-model regressions (p ≤ 0.05). Twenty individuals with type 1 diabetes (7 females) with a mean ± SD age of 35 ± 11 years, body mass index (BMI) 24.8 ± 2.8 kg/m 2 and HbA 1c 54 ± 7 mmol/mol were included. Hypoglycemia/hour (70 mg/dL; <3.9 mmol/L) was similar in both trial arms (12 hrs: 0.07 ± 0.06 vs. 36 hrs: 0.05 ± 0.03, p=0.21). Glycemic excursions during the oral glucose tolerance test were not different after the two fasting periods. Beta-hydroxybutyrate levels were higher after prolonged fasting (p=0.0006). Our study showed that people with type 1 diabetes can safely perform a 36 hours fasting period with a low risk of hypoglycemia and ketoacidosis., Clinical Trial Registration: DRKS.de, identifier DRKS00016148., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moser, Eckstein, Mueller, Tripolt, Yildirim, Abbas, Pferschy, Goswami, Aberer, Obermayer, Pieber, Kojzar, Sourij, Brunner, Niedrist, Herrmann and Sourij.)

To investigate differences in heart rate variability (HRV) during oral glucose tolerance tests (OGTTs) in response to the rate of change in glucose and to different glycaemic ranges in individuals with type 1 diabetes. This was a single-centre, prospective, secondary outcome analysis in 17 individuals with type 1 diabetes (glycated haemoglobin 53 ± 6.3 mmol/L), who underwent two OGTTs (after 12 and 36 hours of fasting) investigating differences in HRV in response to rapid glucose increases/decreases and different glycaemic ranges during OGTT. Based on the rate of change in glucose level, the variables heart rate (P < 0.001), square root of the mean standard difference of successive R-R intervals (P = 0.002), percentage of pairs of R-R intervals with >50 ms difference (P < 0.001) and corrected QT interval (P = 0.04) were significantly altered, with HRV particularly reduced during episodes of rapid glucose rises. Glycaemic ranges during OGTT had no impact on HRV (P < 0.05). Individuals with type 1 diabetes showed no changes in HRV in response to different glycaemic ranges. HRV was dependent on the rate of change in glucose, especially rapid increases in glucose level., (© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The EndoBarrier™ medical device is a duodenal-jejunal bypass liner designed to mimic the effects of gastric bypass surgery to induce weight loss and glycaemic improvement. In this study, 10 participants with type 2 diabetes mellitus (T2DM), a mean body mass index (BMI) of 43.3 ± 5.0 (kg/m 2 ) and a mean glycated haemoglobin A1c (HbA1c) of 60.6 ± 8.6 mmol/mol were examined at baseline (before implantation of EndoBarrier™), 4 weeks after implantation, at 36 weeks (right before explantation) and 24 weeks after the removal of the device to explore the short and long-term effects on glucose metabolism. Besides a significant reduction in body weight and fat mass, EndoBarrier™ treatment significantly improved insulin sensitivity during Botnia clamp investigations after four weeks of implantation. The beneficial effects decreased over time but remained significant 24 weeks after removal of the device.

Objectives: Individuals with type 1 diabetes try to manage the risk of exercise-induced hypoglycemia by either pre-exercise/pre-meal bolus insulin dose reductions and/or consuming additional carbohydrates during exercise. Both strategies have proven to be effective in offsetting hypoglycemia, but it remains unclear which one is more beneficial. The aim of this study was to assess the efficacy of carbohydrate supplementation vs bolus insulin dose reduction in prevention of hypoglycemia during moderate-intensity exercise in those with type 1 diabetes., Methods: This investigation was a retrospective, controlled analysis of 2 independent clinical trials. All participants performed continuous, moderate-intensity cycle ergometer exercise for ∼45 minutes. Two therapy management groups and a control group were compared. Group A was supplemented with 15 to 30 g carbohydrates at a glycemic threshold of 7.0 mmol/L during exercise, group B reduced their individual bolus insulin dose by 50% with their last meal before exercise and group C served as a control., Results: No hypoglycemic events occurred in group A, whereas 4 events were recorded in groups B (p=0.02) and C (p=0.02)., Conclusions: Carbohydrate supplementation was superior to bolus insulin reduction for prevention of hypoglycemia during exercise in people with type 1 diabetes., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Sodium glucose cotransporter 2 (SGLT2) inhibitors are established antidiabetic drugs with proven cardiovascular benefit. Although growing evidence suggests beneficial effects on myocardial remodeling, fluid balance and cardiac function, the impact of empagliflozin initiated early after acute myocardial infarction (AMI) has not been investigated yet. Therefore, the impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial was designed to investigate the efficacy and safety of empagliflozin in diabetic and non-diabetic patients after severe AMI., Methods: Within a multicenter, randomized, double-blind, placebo-controlled, phase 3b trial we will enroll patients with AMI and characteristics suggestive of severe myocardial necrosis are randomized in a 1:1 ratio to empagliflozin (10 mg once daily) or matching placebo. The primary endpoint is the impact of empagliflozin on changes in NT-proBNP within 6 months after AMI. Secondary endpoints include changes in echocardiographic parameters, levels of ketone body concentrations, HbA1c levels and body weight, respectively. Hospitalization rate due to heart failure or other causes, the duration of hospital stay and all-cause mortality will be assessed as exploratory secondary endpoints., Discussion: The EMMY trial will test empagliflozin in patients with AMI regardless of their diabetic status. The EMMY trial may therefore underpin the concept of SGLT2 inhibition to improve cardiac remodeling, pre-and afterload reduction and cardiac metabolism regardless of its antidiabetic effects. Results will provide the rationale for the conduct of a cardiovascular outcome trial to test the effect of empagliflozin in patients with AMI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To investigate the effect of hypoglycaemia on platelet and coagulation activation in people with type 2 diabetes., Materials and Methods: This monocentric, open, single-arm, mechanistic trial included 14 people with established type 2 diabetes (four women, 10 men, age 55 ± 7 years, glycated haemoglobin concentration 51 ± 7 mmol/mol) receiving metformin monotherapy. A stepwise hyperinsulinaemic-hypoglycaemic clamp experiment (3.5 and 2.5 mmol/L, for 30 minutes respectively) was performed, aiming to investigate platelet and coagulation activity during predefined plateaus of hypoglycaemia, as well as 1 day and 7 days later., Results: While platelet activation assessed by light transmittance aggregometry did not significantly increase after the hypoglycaemic clamp procedure, the more sensitive flow cytometry-based measurement of platelet surface activation markers showed hypoglycaemia-induced activation 24 hours (PAC1 pos CD62P pos , PAC1 pos CD63P pos and PAC1 pos CD62P pos CD63 pos ; P < .01) and 7 days after the hypoglycaemic clamp (P < .001 for PAC1 pos CD63 pos ; P < .01 for PAC1 pos CD62P pos and PAC1 pos CD62P pos CD63 pos ) in comparison to baseline. Coagulation markers, such as fibrinogen, D-dimer, plasminogen activator inhibitor-1, von Willebrand factor activity and factor VIII, were also significantly increased, an effect that was most pronounced 24 hours after the hypoglycaemic clamp., Conclusion: A single event of insulin-induced hypoglycaemia led to an increase in markers of platelet activation and coagulation in people with early stages of type 2 diabetes on metformin therapy. However, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycaemic episode., (© 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Steroid-induced hyperglycemia (SIHG) has shown to independently increase the risk for mortality in patients with acute graft-versus-host disease, and it is still unclear whether SIHG might be a modifiable risk factor. Therefore, a feasibility trial was carried out aiming to evaluate the performance of a standardized decision support system (GlucoTab [GT]) for insulin therapy in patients with SIHG. A total of 10 hyperglycemic acute graft-versus-host disease patients were included and treated either with GT or standard of care during hospitalization. Follow-up duration was 6 months. Comparing the GT versus standard of care group, 364 versus 1,020 glucose readings were available during a median of 41 days (interquartile range [IQR] 22-89) and 101 days (IQR 55-147) of hospitalization. The median overall glucose levels were 151 mg/dL (123-192) versus 162 mg/dL (IQR 138-193) for GT and standard of care, respectively (P < 0.001); hypoglycemia rates were comparably low. Treatment of SIHG with an algorithm-based system for subcutaneous insulin was feasible and safe., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Introduction: A 60-cm endoscopically implantable duodenal-jejunal bypass liner (Endobarrier™, GI Dynamics, Lexington, MA, USA) has been introduced as a therapeutic option to support weight loss for a selected group of obese subjects with type 2 diabetes mellitus (T2DM). The sleeve prevents contact between chyme and the intestinal mucosa of the upper gastrointestinal tract. The primary aim of this study is to elucidate the changes in insulin sensitivity and beta-cell function after EndoBarrier™ implantation in obese patients with T2DM; changes in gut permeability and gut microbiome are also to be examined., Methods: This is an open, single-center, prospective trial in which ten obese subjects with T2DM and suboptimal glycemic control (glycosylated hemoglobin A1 c (HbA1c) level > 48 mmol/mol) are investigated with regards to EndoBarrier™ implantation. The Endobarrier™ is implanted shortly after baseline and left in situ for a period of 36 weeks. Dual-energy X-ray absorptiometry measurement, assessment of beta-cell function and insulin sensitivity as measured by a Botnia clamp procedure, and a mixed-meal tolerance test are performed prior to implantation and at 4, 36, and 64 weeks after implantation. The composition of the gut microbiota is characterized from stool using 454 pyrosequencing of 16S rRNA genes. Gut permeability is assessed by a differential sugar absorption method., Planned Outcome: This study will give mechanistic insights in particulr into changes of insulin sensitivity, beta-cell function or microbiome changes over time in subjects implanted with an Endobarrier TM device., Trial Registration: NCT02769728, Registered 12 May 2016. Current Protocol Date/Version: 04 September 2017/Version 1.9.

Background/objectives: Alternate day fasting (ADF) is a subtype of intermittent fasting and is defined as a continuous sequence of a fast day (100% energy restriction, zero calories) and a feed day (ad libitum food consumption), resulting in roughly 36-h fasting periods. Previous studies demonstrated weight reductions and improvements of cardiovascular risk factors with ADF in obese subjects. However, rigorous data on potential endocrine, metabolic and cardiovascular effects, besides weight loss, are lacking. Therefore we aim to investigate the short- and mid- to long-term clinical and molecular effects of ADF in healthy non-obese subjects., Methods: We will perform a prospective cohort study with an embedded randomized controlled trial (RCT) including 90 healthy subjects. Thirty of them will have performed ADF for at least 6 months (mid-term group). Sixty healthy subjects without a particular diet before enrolment will serve as the control group. These subjects will be 1:1 randomized to either continuing their current diet or performing ADF for 4 weeks. All subjects will undergo study procedures that will be repeated in RCT participants after 4 weeks. These procedures will include assessment of outcome parameters, dual-energy X-ray absorptiometry, measurement of endothelial function, an oral glucose tolerance test, 24-h blood pressure measurement, retinal vessel analysis, echocardiography and physical activity measurement by an accelerometer. Blood, sputum, buccal mucosa and faeces will be collected for laboratory analyses. Participants in the RCT will wear a continuous glucose monitor to verify adherence to the study intervention., Planned Outcomes: The aim of this project is to investigate the effects of ADF on human physiology and molecular cellular processes. This investigation should gain in-depth mechanistic insights into the concept of ADF and form the basis for larger subsequent cohort recruitment and consecutive intervention studies., Trial Registration: NCT02673515; registered 24 November 2015. Current protocol date/version: 7 February 2017/version 1.8.