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AimsSodium–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 resultsIn 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.ConclusionIn 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.

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 therapy3 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.

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.This prospective, multicentre cohort study analysed people with type 1 and type 2 diabetes and a glycated haemoglobin level ≤58 mmol/mol (7.5%) or58 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.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.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.

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.

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 50 ms difference (P

Background and aims: Regular physical activity and exercise represent a corner stone in the treatment of type 1 diabetes (T1D) , however, exercise-induced hypoglycemia remains the major barrier to a physically active lifestyle. Therefore, the ULTRAFLEXI-1 study compared two basal insulin analogues, Glargine 300U/ml (IGlar U300) and Degludec (IDeg) , in two different doses (100% and 75% of the regular dose) when used around spontaneous exercise sessions in adults with T1D. Methods: We performed a randomized, single-center, four-period, cross-over trial (EudraCT: 2019-003209-89) and included adults with T1D treated with multiple daily insulin injections and an HbA1c ≤10% (≤86 mmol/mol) . In each of the four 2-weeks-periods, participants attended six spontaneous evening cycling sessions (60 minutes, moderate intensity) . The days of exercising were randomized and announced at 8 A.M. to the participants. The basal insulin used on the exercise days during the four periods were: IGlar U300 100% or 75% of the regular dose or IDeg 100% or 75%, respectively. 100% of the regular basal insulin dose was used at all non-exercise days. CGM was performed using a blinded Dexcom G6 device. The primary outcome was TBR ( Results: 25 people were enrolled (14 male) , aged 41.4±11.9 years, with a mean diabetes duration of 16.8±10.4 years and a mean HbA1c of 7.5±0.8%. (59±9 mmol/mol) . Mean TBR during the 24-hour periods following the exercise sessions was 2.71±2.56% for IGlar U300 (100%) and 4.37%±3.43% for IDeg (100%) (p=0.025) as well as 2.28±2.67% for IGlar U300 compared to 2.55 ±2.87% with IDeg when using the 75% dose on exercise days (p=0.720) . Conclusion: Time spent in hypoglycemia after spontaneous exercise sessions was significantly lower in people with type 1 diabetes receiving IGlar U300 as compared to IDeg when the 100% dose was used. Disclosure O. Moser: Research Support; Dexcom, Inc., Sanofi, Speaker’s Bureau; Medtronic. M. L. Eckstein: None. L. Hönger: None. J. Lenz: None. I. Mursic: None. C. Sternad: None. M. Zanker: None. H. Ziko: None. P. N. Pferschy: None. N. J. Tripolt: None. H. Sourij: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker’s Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk. A. Mueller: None. F. Aberer: Other Relationship; Amgen Inc., Boehringer Ingelheim International GmbH, Sanofi. F. Aziz: None. H. Kojzar: None. C. Sourij: None. A. M. Obermayer: None. F. M. Abbas: None. P. Birnbaumer: None. Funding Sanofi-aventis (DCV-2018-12349)

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 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, 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.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.

Vaccination and potentially related side effects might impact glucose management in people with diabetes. In this study, we investigated effects of COVID-19 vaccination on glycemia assessed by continuous glucose monitoring (CGM) in people with type 1 and type 2 diabetes. 74 participants of the ongoing multicenter prospective COVAC-DM-study, investigating the immune response to COVID-19 vaccines in people with diabetes, were willing to participate in this CGM sub-study. Time spent in glycemic ranges (time in range [TIR] 70-180 mg/dL; time below range [TBR] 180 mg/dL) was assessed daily from two days prior to three days after the first COVID-19 vaccination. Participants were asked to document side effects in response to vaccination, insulin injections, and carbohydrate intake. 58 participants with type 1 (27 female, mean age 39.5 years, HbA1c 57 ± 12 mmol/mol) and 16 with type 2 diabetes (9 females, mean age 60.6 years, HbA1c 63 ± 11mmol/mol) were included in this study. The mean TIR did not change on the day of the vaccination and the following 3 days (p>0.05). In people with type 1 diabetes, the TIR (p=0.033) and the TAR (p= 0.043) deteriorated on days with side effects as compared to those without. Side effects occurring after COVID-19 vaccination significantly reduce the TIR and increase the TAR in people with type 1 diabetes, while no impact was observed in people with type 2 diabetes.

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.

AimsImmune response to COVID-19 vaccination and a potential impact of glycaemia on antibody levels in people with diabetes remains unclear. We investigated 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 analysed the response in comparison to individuals without diabetes.Materials and MethodsThis prospective, multicenter cohort study analysed people with type 1 and type 2 diabetes, well (HbA1cResults86 healthy controls and 161 participants with diabetes were enrolled, 150 (75 with type 1 diabetes and 75 with type 2 diabetes) were eligible for the analysis. After the first vaccination, only 52.7% in the type 1 diabetes group and 48.0% in the type 2 diabetes group showed antibody levels above the cut-off for positivity. Antibody levels after the second vaccination were similar in people with type1, type 2 diabetes and healthy controls if adjusted for age, sex and multiple testing (p>0.05). Age (r=−0.45, pConclusionsAnti-SARS-CoV-2 S antibody levels after the second vaccination were comparable in healthy controls, people with type 1 and type 2 diabetes, irrespective of glycaemic control. Age and renal function correlated significantly with the extent of antibody levels.

Background and aim 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. Since SGLT2 receptors are not expressed in human myocardium, these cardioprotective effects be indirect or pleiotropic. Besides metabolic effects anti-inflammatory anti-fibrotic properties are discussed. Despite a strong correlation of ventricular arrhythmias with HFrEF, the impact of ertugliflozin on the 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 diabetic and non-diabetic HFrEF patients. Methods 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 HFrEF or HFmrEF and ICD±CRT therapy >3 months and previous ventricular tachycardia (at least 10 documented non-sustained VT episodes within the last 12 months) are randomized in a 1:1 ratio to ertugliflozin (5mg 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 be the number of therapeutic interventions of implanted devices, atrial fibrillation, heart failure biomarker and changes in physical function quality of life, stress and anxiety. Conclusion The ERASe trial will be the first trial to test ertugliflozin in heart failure patients with non-preserved 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 reverse remodelling, including reduced arrhythmic burden. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): unrestricted grant of MSD

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/m2 and HbA1c 54 ± 7 mmol/mol were included. Hypoglycemia/hour (70 mg/dL

The sodium-glucose cotransporter 2 inhibitors (SGLT2i), empagliflozin, dapagliflozin, and canagliflozin, have shown impressive beneficial effects in patients with type 2 diabetes mellitus in mandatory cardiovascular outcome trials. Retrospective data analysis revealed signals that pointed towards positive effects independent of the antidiabetic effects. This could be confirmed for empagliflozin and dapagliflozin in chronic heart failure with reduced ejection fraction alone, where rates of hospitalization for heart failure and cumulative major adverse cardiovascular events were reduced to a similar extent in patients with and without diabetes mellitus as in corresponding outcome trials. Cardiac remodeling following myocardial infarction leads to heart failure with reduced ejection fraction in many patients and aggravates morbidity and mortality. Clinical data of SGLT2i treatment after acute myocardial infarction is sparse. This review focuses on available experimental data on the effects of SGLT2i used before, during, and after myocardial infarction as well as already published and currently ongoing clinical trials.

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/m2) 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.

Aim To assess predictors of in‐hospital mortality in people with prediabetes and diabetes hospitalized for COVID‐19 infection and to develop a risk score for identifying those at the greatest risk of a fatal outcome. Materials and Methods A combined prospective and retrospective, multicentre, cohort study was conducted at 10 sites in Austria in 247 people with diabetes or newly diagnosed prediabetes who were hospitalized with COVID‐19. The primary outcome was in‐hospital mortality and the predictor variables upon admission included clinical data, co‐morbidities of diabetes or laboratory data. Logistic regression analyses were performed to identify significant predictors and to develop a risk score for in‐hospital mortality. Results The mean age of people hospitalized (n = 238) for COVID‐19 was 71.1 ± 12.9 years, 63.6% were males, 75.6% had type 2 diabetes, 4.6% had type 1 diabetes and 19.8% had prediabetes. The mean duration of hospital stay was 18 ± 16 days, 23.9% required ventilation therapy and 24.4% died in the hospital. The mortality rate in people with diabetes was numerically higher (26.7%) compared with those with prediabetes (14.9%) but without statistical significance (P = .128). A score including age, arterial occlusive disease, C‐reactive protein, estimated glomerular filtration rate and aspartate aminotransferase levels at admission predicted in‐hospital mortality with a C‐statistic of 0.889 (95% CI: 0.837‐0.941) and calibration of 1.000 (P = .909). Conclusions The in‐hospital mortality for COVID‐19 was high in people with diabetes but not significantly different to the risk in people with prediabetes. A risk score using five routinely available patient variables showed excellent predictive performance for assessing in‐hospital mortality.

AIMWe assessed predictors of in-hospital mortality in people with prediabetes and diabetes hospitalized for COVID-19 infection and developed a risk score for identifying those at the highest risk of a fatal outcome.MATERIALS AND METHODSA combined prospective and retrospective multicenter cohort study was conducted in 10 sites in Austria on 247 people with diabetes or newly diagnosed prediabetes, who were hospitalised for COVID-19. The primary outcome was in-hospital mortality and predictor variables at the time of admission included clinical data, comorbidities of diabetes or laboratory data. Logistic regression analyses were performed to identify significant predictors and develop a risk score for in-hospital mortality.RESULTSThe mean age of people hospitalized (n=238) for COVID-19 was 71.1 ± 12.9 years, 63.6% were males, 75.6% had type 2 diabetes, 4.6% had type 1 diabetes, and 19.8% had prediabetes. The mean duration of hospital stay was 18 ± 16 days, 23.9% required ventilation therapy, and 24.4% died in the hospital. Mortality rate in people with diabetes was numerically higher (26.7%) as compared to those with prediabetes (14.9%) but without statistical significance (p=0.128). A score including age, arterial occlusive disease, CRP, eGFR and AST levels at admission predicted in-hospital mortality with a C-statistics of 0.889 (95%CI: 0.837 – 0.941) and calibration of 1.000 (p=0.909).CONCLUSIONSThe in-hospital mortality for COVID-19 was high in people with diabetes and not significantly different to the risk in people with prediabetes. A risk score using five routinely available patient parameters demonstrated excellent predictive performance for assessing in-hospital mortality.

Background: Metabolic regulation of glucose can be altered by fasting periods. The aim of our study was to examine the glucose metabolism after an overnight fast (12 hours) as well as after prolonged fasting (36 hours of fasting) in non-obese people, people with obesity and people with type 2 diabetes (T2DM). Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after 12 and 36 hours fasting, respectively. Area under the curve (AUC) was calculated according to the trapezoidal rule. Insulin sensitivity was estimated by using QUICKI and HOMA-IR. Results: In total 60 participants (age 43±16 years, 62% women) were included. Fasting levels of glucose, insulin and c-peptide were significantly lower in all cohorts after 36 hours vs. 12 hours of fasting (p Conclusion: Our data demonstrate higher glucose excursions and a reduced early insulin response after 36 hours of fasting compared to an overnight fasting period in participants with various glucose tolerance levels. Disclosure N.J. Tripolt: None. P.N. Pferschy: None. A. Obermayer: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. H. Kojzar: None. C. Sourij: None. O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. B.M. Obermayer-Pietsch: None. R. Riedl: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.

Evidence is accumulating that prolonged fasting (PL) might evoke improvements in metabolic health. Since fasting is accompanied by numerous endogenous processes to equilibrate blood glucose concentration, its feasibility is disputable in people with type 1 diabetes (PWT1D). We aimed to assess the safety and efficacy of PL in c-peptide negative (^< 0.9 ng/mL) PWT1D. Methods: Glucose metabolism was assessed during the fasting period (CGM) and via a 75 g OGTT accompanied with the same bolus insulin dose after 12 (shortF) and 36 hours of fasting (longF). Area under the curve (AUC) was calculated following the trapezoidal rule. Safety was assessed by the number of hypoglycemic episodes (< 70 mg/dL) during fasting. Data were analysed using a paired sample t-test or Mann-Whitney-U-test (p≤0.05). Results: In total, 17 PWT1D (6 women, aged 37 ± 11 years, BMI 24.9 ± 2.9 kg/m2, 10 MDI) were included. 13 episodes of mild hypoglycemia occurred in 9 participants during the shortF versus 27 in 15 participants during the longF. Incidence of hypoglycemia per hour was similar in both arms (median [IQR] shortF: 0.08 [0 - 0.08] vs. longF: 0.06 [0.03 - 0.07], p=0.62). Conclusion: PL did not increase the risk of hypoglycemia in PWT1D. Intriguingly, the AUC for glucagon was significantly higher after longF compared to shortF, potentially explaining the numerically lower number of hypoglycemic events during longF. Disclosure O. Moser: Other Relationship; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi. N.J. Tripolt: None. P.N. Pferschy: None. A. Obermayer: None. H. Kojzar: None. J.K. Mader: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Medtronic, Prediktor Medical, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. M. Brunner: None. A. Mueller: None. H. Yildirim: None. C. Sourij: None. M.L. Eckstein: Research Support; Self; Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi.

IntroductionTo investigate the glycaemic response, macronutrient intake and insulin management in people with type 1 diabetes (T1D) compared to healthy individuals around a running competition.Material and methodsThis was a single-centre, prospective, controlled observational study performed in individuals with T1D and healthy people. 24 people (12 T1D) were included in this study (age: T1D 41±12 vs. healthy 38±6 years, females: 3 vs. 6, BMI: 25.53.0 vs. 22.9±2.8 kg/m2). Both groups received an intermittently scanned continuous glucose monitoring (isCGM; FreeStyle Libre 1, Abbott, USA) system to assess glycaemia 24 hours before, during and 24 hours after a running competition. During this period, participants recorded their food intake and insulin administration. Data were analysed via ANOVA and mixed model analyses with post-hoc testing (p≤0.05).ResultsFor overall glycaemic ranges in comparison of groups, significant differences were found for time in range (T1D 63±21% vs. healthy 89±13%, p = 0.001), time above range (TAR) 1 (T1D 21±15% vs. healthy 0±0%, pConclusionPeople with T1D have impaired glucose responses around a running competition compared to healthy individuals. However, basal insulin dose reductions were sufficient to prevent further dysglycaemia.Clinical trial iddrks.de; DRKS00019886.

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.

Background Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements. Methods In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c l-arginine divided by the sum of (l-ornithine plus l-citrulline). The AOR was calculated by dividing l-arginine by l-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances. Results We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. − 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549). Conclusion Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 (https://clinicaltrials.gov/ct2/show/NCT02350478)

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.

PurposeDiabesity, the combination of obesity and type 2 diabetes, is an ever-growing global health burden. Diabesity-associated dysbiosis of the intestinal microbiome has gained attention as a potential driver of disease and, therefore, a possible therapeutic target by means of pro- or prebiotic supplementation. This study tested the effects of a multispecies synbiotic (i.e. a combination of probiotics and prebiotics) on glucose metabolism, gut microbiota, gut permeability, neutrophil function and quality of life in treatment-experienced diabesity patients.MethodsA randomized, double-blind, placebo-controlled pilot study with 26 diabesity patients was conducted in which patients received a daily dose of a multispecies probiotic and a prebiotic (or a placebo) for 6 months.ResultsThere were no changes in glucose metabolism or mixed meal tolerance test responses throughout the study. The analysis of secondary outcomes revealed beneficial effects on hip circumference [− 1 (95% CI − 4; 3) vs +3 (− 1; 8) cm, synbiotics vs. placebo, respectively,p = 0.04], serum zonulin [− 0.04 (− 0.2; 0.1) vs +0.3 (− 0.05; 0.6) ng/ml,p = 0.004)] and the physical role item of the SF36 quality of life assessment [+ 5.4 (− 1.7; 12.5) vs − 5.0 (− 10.1; 0.2) points,p = 0.02] after 3 months of intervention, and lipoprotein (a) [− 2.1 (− 5.7; 1.6) vs +3.4 (− 0.9; 7.9) mg/dl,p = 0.02] after 6 months. There were no significant differences in alpha or beta diversity of the microbiome between groups or time points.ConclusionsGlucose metabolism as the primary outcome was unchanged during the intervention with a multispecies synbiotic in patients with diabesity. Nevertheless, synbiotics improved some symptoms and biomarkers of type 2 diabetes and aspects of quality of life suggesting a potential role as adjuvant tool in the management of diabesity.Graphic abstract

Objective: Although hypoglycemia is associated with increased risk for subsequent cardiovascular events, experimental data investigating the effect of hypoglycemia on coagulation and platelet activation in type 2 diabetes are limited. Research Design and Methods: This monocentric, open, single arm, trial included 14 subjects with type 2 diabetes (10 male/4 female, age 55±7 years, HbA1c 51±7 mmol/mol, diabetes duration 5±4 years) and metformin treatment only. A stepwise hyperinsulinemic hypoglycemic clamp was performed, aiming to investigate parameters of platelet function during predefined plateaus of hypoglycemia (at 63 and 45 mg/dl, for 30 minutes respectively), 24 hours and 7 days later. Additionally, all subjects underwent a hyperinsulinemic euglycemic clamp experiment. Results: While platelet activation assessed by light transmittance aggregometry did not significantly increase following a hypoglycemic clamp, flow cytometry based platelet activation assessment demonstrated a significant increase 24 hours (PAC1CD62PCD63pos p Conclusions: One single event of insulin induced hypoglycemia led to an increase in markers of platelet activation and coagulation, however, the activation occurred with a delay and was evident 24 hours and 7 days after the actual hypoglycemia. Disclosure F. Aberer: None. P.N. Pferschy: None. N.J. Tripolt: None. C. Sourij: None. H. Kojzar: None. B. Prietl: None. S. Kofler: None. M. Brunner: None. R. Riedl: None. E. Novak: None. A.M. Obermayer: None. P. Reitbauer: None. T. Stojakovic: None. F. Aziz: None. A. Oulhaj: None. F. Pruller: None. H. Scharnagl: Research Support; Self; Abbott, Amgen Inc. Speaker's Bureau; Self; Sanofi-Aventis Deutschland GmbH. H. Sourij: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi-Aventis. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis.

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.

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 (PAC1pos CD62Ppos , PAC1pos CD63Ppos and PAC1pos CD62Ppos CD63pos ; P

Summary Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study ( ClinicalTrials.gov identifier: NCT02673515 ), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.

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 A1c (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 EndobarrierTM device. Trial registration NCT02769728, Registered 12 May 2016. Current Protocol Date/Version: 04 September 2017/Version 1.9.

Background: It is well known that the metabolic regulation of glucose can be influenced by dietary interventions, including alterations in meal timing. Aim of our analysis was to examine the glucose metabolism after an overnight fast (10 hours) and after prolonged fasting (36 hours of fasting). Material and Methods: Glucose metabolism was assessed by a 75 g oral glucose tolerance test after an overnight fasting period of 10 hours and a fasting period of 36h. Beta-cell function was quantified by 1st and 2nd phase insulin secretion indices. Results: We included 37 healthy subjects (mean age 48±10 years; 54% women) with a mean body mass index (BMI) of 25.2±3.4 kg/m2. After prolonged fasting mean 2h-glucose and AUC for glucose value were significantly higher than after 10h fasting (2h-glucose: 110±27 mg/dL vs. 89±24 mg/dL; p Conclusion: Our data demonstrate higher glucose excursions and a reduced insulin response after a 36 hour fasting period as compared to an overnight fasting period in healthy subjects.After 10h fastingAfter 36h fastingp-valueFasting c-peptide (ng/mL)1.39 ± 0.651.09 ± 1.030.025Fasting insulin (mU/L)7.9 ± 5.15.7 ± 5.80.042Fasting glucose (mg/dL)88 ± 988 ± 180.830Insulin after 60min (mU/L)87.6 ± 85.853.4 ± 51.80.0361st phase insulin secretion982 ± 573745 ± 5000.012HOMA-IR1.75 ± 1.181.39 ± 2.070.303Stumvoll index (ISI)0.10 ± 0.030.09 ± 0.03 0.230 Disclosure N.J. Tripolt: None. S. Stekovic: None. J. Url: None. F. Aberer: None. P.N. Pferschy: None. R. Riedl: None. B.M. Obermayer-Pietsch: None. T.R. Pieber: Consultant; Self; Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Employee; Self; CBmed. Research Support; Self; Novo Nordisk A/S, AstraZeneca. F. Madeo: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..

Background: A 60cm endoscopically implantable, duodeno-jejunal bypass liner (Endobarrier®) has been introduced as a therapeutic option for obese subjects with type 2 diabetes (T2DM). The aim of the study was to explore short and mid-term metabolic effects in the clamp setting. Materials and Methods: This open, single-center trial investigated 10 obese, T2DM subjects with suboptimal glycemic control (HbA1c >48mmol/mol). Prior to the implantation of the gastrointestinal liner (baseline), 4 weeks and 9 months (explantation) after, all subjects underwent Dual-energy X-ray absorptiometry (DXA) measurement, assessment of beta cell function and insulin sensitivity by a Botnia clamp procedure and a mixed-meal tolerance test. Results: We investigated 10 patients with a mean age of 48±9 years and mean diabetes duration of 7±6 years. Detailed results and changes over the time are given in Table. No device has been removed prematurely. Conclusion: Treating obese T2DM subjects by an endoluminally implanted Endobarrier® leads to moderate weight reduction with large inter-individual variation. Significant improvements in insulin sensitivity occurred already 4 weeks after the Endobarrier® implantation, which were maintained until the explantation of the device, accompanied by reductions in blood pressure.Baseline (mean±SD)4 Weeks (mean±SD)9 Monhts (mean±SD)p-value (Group comparison baseline vs. 4 weeks)p-value (Group comparison baseline vs. 9 months)Body weight (kg)121.2 ± 18.5116.3 ± 18.2115.7± 22.5 Disclosure N.J. Tripolt: None. F. Aberer: None. J. Url: None. P.N. Pferschy: None. C. Högenauer: None. F. Schreiber: None. A. Eherer: None. E. Svehlikova: None. C. Sourij: None. A.M. Obermayer: None. V. Stadlbauer: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..

Aims: To investigate the effects of the DPP-4 inhibitor Linagliptin in subjects with coronary artery disease (CAD) and early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements. Materials and Methods: In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2h glucose >200mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy, HbA1c Results: We investigated 43 patients with a mean age of 6±8 years. FMD at baseline was 3.5±3.1% in the Linagliptin group vs. 4.0±2.9% in the placebo group. The change in mean FMD in the Linagliptin group (0.4±4.8%) was not significantly different compared to the change in the placebo group (-0.45±3.01%; p=0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR); p=0.6and AOR; p=0.549), body weight, blood pressure and lipid parameters. Of note, HbA1c was significantly reduced in the linagliptin group (-1.5 vs. -0.4; p=0.026). Conclusion: Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or GABR. Disclosure F. Aberer: None. N.J. Tripolt: None. J. Url: None. R. Hödl: None. G. Dimsity: None. F. Aziz: None. R. Riedl: None. F. Hafner: None. D. Strunk: None. T. Stojakovic: None. M. Brodmann: None. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc..